What are the causes of hypoglycemia in liver failure. How does liver damage impact blood sugar regulation. What symptoms indicate hypoglycemia in patients with liver disease. Which treatment approaches can help manage hypoglycemia in liver failure patients.

The Critical Role of the Liver in Blood Sugar Regulation

The liver plays a pivotal role in maintaining stable blood glucose levels. It acts as a glucose storage and production center, helping to prevent both hyperglycemia and hypoglycemia. When blood sugar levels drop, the liver releases stored glucose through a process called glycogenolysis. Additionally, it can produce new glucose molecules through gluconeogenesis when glycogen stores are depleted.

In patients with liver failure or severe liver damage, these crucial glucose-regulating functions become impaired. This makes individuals with liver disease particularly susceptible to dangerous drops in blood sugar, known as hypoglycemia.

Mechanisms Behind Hypoglycemia in Liver Failure

Several factors contribute to the development of hypoglycemia in patients with liver failure:

• Impaired glycogen storage and release
• Reduced gluconeogenesis capacity
• Insulin resistance and hyperinsulinemia
• Increased peripheral glucose utilization
• Malnutrition and reduced caloric intake

As liver function deteriorates, the organ’s ability to store glycogen and produce glucose becomes severely limited. This leaves patients vulnerable to rapid drops in blood sugar, especially during periods of fasting or increased metabolic demand.

The Paradox of Insulin Resistance

Interestingly, many patients with advanced liver disease develop insulin resistance, leading to hyperinsulinemia. While this might seem counterintuitive to hypoglycemia development, it actually exacerbates the problem. The high insulin levels suppress gluconeogenesis and glycogenolysis in the liver, further compromising the body’s ability to maintain stable glucose levels.

Identifying Hypoglycemia in Liver Failure Patients

Recognizing hypoglycemia in patients with liver failure can be challenging, as symptoms may overlap with other complications of liver disease. However, prompt identification is crucial for preventing serious consequences.

Common Symptoms of Hypoglycemia

• Confusion and altered mental status
• Sweating and tremors
• Weakness and fatigue
• Blurred vision
• Headache
• Irritability or mood changes
• In severe cases, seizures or loss of consciousness

It’s important to note that some liver failure patients may experience “hypoglycemia unawareness,” where the typical warning signs are absent or diminished. This makes regular blood glucose monitoring even more critical for these individuals.

Risk Factors for Hypoglycemia in Liver Disease

While any patient with liver failure is at risk for hypoglycemia, certain factors can increase susceptibility:

1. Advanced cirrhosis or end-stage liver disease
2. Malnutrition or prolonged fasting
3. Alcohol abuse
4. Certain medications (e.g., beta-blockers, ACE inhibitors)
5. Concurrent infections or sepsis
6. Recent surgery or trauma
7. Presence of hepatocellular carcinoma

Elderly patients with low body weight are particularly vulnerable to hypoglycemia in the setting of liver injury, as highlighted in recent case reports. Their reduced glycogen stores and diminished capacity for gluconeogenesis make them especially susceptible to rapid drops in blood sugar.

Diagnostic Approaches for Hypoglycemia in Liver Failure

Accurate diagnosis of hypoglycemia in liver failure patients requires a combination of clinical assessment and laboratory testing.

Key Diagnostic Steps

• Regular blood glucose monitoring, especially during fasting periods
• Measurement of serum insulin and C-peptide levels
• Evaluation of counterregulatory hormones (glucagon, cortisol, growth hormone)
• Assessment of liver function through standard liver enzyme tests
• Imaging studies to evaluate liver structure and identify potential tumors

In some cases, specialized tests like the glucagon stimulation test or mixed meal tolerance test may be necessary to fully characterize the nature of the hypoglycemia.

Treatment Strategies for Hypoglycemia in Liver Failure

Managing hypoglycemia in patients with liver failure requires a multifaceted approach that addresses both immediate glucose needs and underlying liver dysfunction.

Acute Management

• Oral glucose administration for conscious patients
• Intravenous dextrose for severe hypoglycemia or unconscious patients
• Glucagon injection in emergency situations

Long-term Management

• Frequent small meals and bedtime snacks to maintain steady glucose levels
• Dietary modifications to ensure adequate carbohydrate intake
• Consideration of continuous glucose monitoring systems
• Management of underlying liver disease to improve overall function
• Cautious use of medications that may affect glucose metabolism

In some cases, medications like diazoxide or octreotide may be considered to help manage recurrent hypoglycemia, though their use must be carefully weighed against potential side effects in the context of liver disease.

The Impact of Hypoglycemia on Prognosis in Liver Failure

Hypoglycemia can have serious consequences for patients with liver failure, potentially exacerbating existing complications and worsening overall prognosis. Recent research has highlighted the increased risk of mortality associated with severe hypoglycemic events in patients with liver injury.

Key Findings from Recent Studies

• Patients with type 2 diabetes and acute liver injury who experience severe hypoglycemia have a significantly higher risk of mortality
• The risk of death is particularly elevated in the first 30 days following a hypoglycemic event
• Recurrent episodes of hypoglycemia may contribute to progressive cognitive decline and increased frailty in liver failure patients

These findings underscore the importance of vigilant glucose monitoring and proactive management strategies in patients with liver disease, especially those with additional risk factors like diabetes or advanced age.

Preventing Hypoglycemia in Liver Failure Patients

While complete prevention of hypoglycemia may not always be possible in liver failure patients, several strategies can help minimize the risk:

1. Regular and frequent blood glucose monitoring
2. Structured meal plans with consistent carbohydrate intake
3. Education of patients and caregivers on recognizing and responding to hypoglycemia symptoms
4. Avoidance of prolonged fasting periods
5. Careful medication management to avoid drugs that may exacerbate hypoglycemia risk
6. Addressing malnutrition through appropriate nutritional support
7. Optimizing management of underlying liver disease

For patients with recurrent or severe hypoglycemia, more intensive interventions like continuous glucose monitoring or consideration of liver transplantation may be necessary.

Future Directions in Research and Management

As our understanding of the complex interplay between liver function and glucose metabolism continues to evolve, several areas of research hold promise for improving the management of hypoglycemia in liver failure patients:

• Development of liver-specific glucose-regulating medications
• Refinement of artificial liver support systems to better maintain glucose homeostasis
• Exploration of stem cell therapies to restore liver function and glucose regulation
• Improved predictive models to identify patients at highest risk for severe hypoglycemia
• Investigation of the long-term cognitive and functional impacts of recurrent hypoglycemia in liver disease

Ongoing research in these areas may lead to more targeted and effective strategies for preventing and managing hypoglycemia in the context of liver failure, ultimately improving outcomes for this vulnerable patient population.

Tailoring Management Approaches for Different Etiologies of Liver Failure

The underlying cause of liver failure can significantly impact the risk and management of hypoglycemia. Different etiologies may require tailored approaches to glucose regulation:

Alcoholic Liver Disease

Patients with alcoholic liver disease are particularly susceptible to hypoglycemia due to several factors:

• Depleted glycogen stores from chronic malnutrition
• Impaired gluconeogenesis due to alcohol’s effects on liver metabolism
• Potential for concurrent pancreatitis affecting insulin production

Management in these patients often focuses on addressing nutritional deficiencies and supporting alcohol cessation to improve overall liver function and glucose regulation.

Viral Hepatitis

In cases of acute viral hepatitis leading to liver failure, hypoglycemia may be a transient issue that resolves as liver function improves. However, in chronic cases progressing to cirrhosis, long-term glucose management strategies become necessary.

Autoimmune Hepatitis

Patients with autoimmune hepatitis may face additional challenges due to the use of corticosteroids in treatment, which can affect glucose metabolism. Careful monitoring and adjustment of immunosuppressive regimens may be necessary to balance disease control and glucose stability.

Hepatocellular Carcinoma

Liver tumors can cause hypoglycemia through various mechanisms, including increased glucose utilization and production of insulin-like growth factors. Management in these cases may involve tumor-directed therapies in addition to glucose regulation strategies.

Understanding the specific etiology of liver failure allows healthcare providers to anticipate potential complications and tailor management strategies accordingly, potentially improving outcomes for patients at risk of hypoglycemia.

The Role of Nutritional Support in Preventing Hypoglycemia

Proper nutritional support is crucial in managing and preventing hypoglycemia in liver failure patients. Malnutrition is common in advanced liver disease and can exacerbate the risk of low blood sugar episodes.

Key Nutritional Considerations

• Adequate calorie intake to support energy needs and prevent muscle catabolism
• Balanced macronutrient distribution with attention to carbohydrate consistency
• Supplementation of branched-chain amino acids to support protein synthesis and glucose regulation
• Micronutrient supplementation to address deficiencies common in liver disease

In some cases, enteral or parenteral nutrition may be necessary to ensure consistent nutrient delivery and maintain stable blood glucose levels. Consultation with a registered dietitian specializing in liver disease can be invaluable in developing an optimal nutritional plan.

Timing and Frequency of Meals

Structuring meal timing and frequency is essential for maintaining stable glucose levels in liver failure patients:

1. Small, frequent meals throughout the day to provide a steady supply of glucose
2. A bedtime snack to help prevent nocturnal hypoglycemia
3. Consideration of continuous enteral feeding in severe cases

By optimizing nutritional support and meal planning, healthcare providers can help reduce the frequency and severity of hypoglycemic episodes in patients with liver failure, potentially improving overall outcomes and quality of life.

Hypoglycemia in Liver Failure: Causes, Symptoms, and Treatment

If you have liver failure, you may be at risk for hypoglycemia, a condition where your blood sugar levels drop too low. Hypoglycemia can be dangerous and even life-threatening if left untreated. In this blog post, we’ll explore the causes, symptoms, and treatment of hypoglycemia in liver failure.

Causes of Hypoglycemia in Liver Failure

Hypoglycemia in liver failure is caused by a combination of factors. The liver plays a crucial role in regulating blood sugar levels by producing and storing glucose. When the liver is damaged, it can’t perform this function effectively, leading to low blood sugar levels.

Other factors that can contribute to hypoglycemia in liver failure include:

• Medications that affect blood sugar levels
• Skipping meals or not eating enough
• Excessive alcohol consumption
• Insulin resistance

Symptoms of Hypoglycemia in Liver Failure

The symptoms of hypoglycemia in liver failure can vary depending on the severity of the condition. Some common symptoms include:

• Sweating
• Trembling
• Confusion
• Dizziness
• Headache
• Irritability
• Blurred vision
• Fatigue

If you experience any of these symptoms, it’s important to seek medical attention right away.

Treatment of Hypoglycemia in Liver Failure

The treatment of hypoglycemia in liver failure depends on the underlying cause of the condition. In some cases, simply eating a snack or meal can help raise blood sugar levels. In other cases, medication may be necessary to regulate blood sugar levels.

At Nao Medical, we offer comprehensive care for liver health. Our team of healthcare professionals can help diagnose and treat hypoglycemia in liver failure, as well as provide ongoing care to manage the condition.

Book an Appointment with Nao Medical

If you’re experiencing symptoms of hypoglycemia in liver failure, don’t wait until it’s too late. Book an appointment with Nao Medical today to get the care you need for your liver health. Our same-day appointments, minimal wait times, and exceptional staff make it easy to get the care you need when you need it.

External Resources

For more information on diabetes and blood sugar management, check out these external resources:

• CDC Diabetes Basics
• American Diabetes Association

Key Takeaways

• Hypoglycemia in liver failure is caused by a combination of factors, including liver damage and medication use.
• Symptoms of hypoglycemia in liver failure can include sweating, trembling, confusion, and dizziness.
• Treatment of hypoglycemia in liver failure depends on the underlying cause of the condition.
• Nao Medical offers comprehensive care for liver health, including diagnosis and treatment of hypoglycemia in liver failure.

Disclaimer: The information presented in this article is intended for general informational purposes only and should not be considered, construed or interpreted as legal or professional advice, guidance or opinion.

The Risk of Severe Hypoglycemia and Mortality in Patients With Type 2 Diabetes and Discharged With Acute Liver Injury | Diabetes Care

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Clinical Care/Education/Nutrition/Psychosocial Research|
November 15 2022

Fu-Shun Yen

;

Ming-Chih Hou

;

Chun-Wei Pan;

Jia-Sin Liu

;

Chih-Cheng Hsu

;

Chii-Min Hwu

Corresponding authors: Chih-Cheng Hsu, [email protected], and Chii-Min Hwu, [email protected]

Diabetes Care 2023;46(1):20–27

https://doi.org/10.2337/dc22-1349

Article history

Received:

July 11 2022

Accepted:

October 16 2022

PubMed:

36378550

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Citation

Fu-Shun Yen, Ming-Chih Hou, Chun-Wei Pan, Jia-Sin Liu, Chih-Cheng Hsu, Chii-Min Hwu; The Risk of Severe Hypoglycemia and Mortality in Patients With Type 2 Diabetes and Discharged With Acute Liver Injury. Diabetes Care 2 January 2023; 46 (1): 20–27. https://doi.org/10.2337/dc22-1349

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OBJECTIVE

To compare the risks of severe hypoglycemia and mortality between patients with type 2 diabetes (T2D) and discharged with and without acute liver injury.

RESEARCH DESIGN AND METHODS

From 1 January 2000 to 31 December 2010, we identified patients with T2D and hospitalization for acute liver injury and hospitalization for other causes from the National Health Insurance Research Database of Taiwan. Multivariable-adjusted Cox proportional hazards models were used to compare the risks of severe hypoglycemia and mortality between the study and control groups.

RESULTS

The incidence rates and adjusted hazard ratios (aHRs) for severe hypoglycemia within 90 days and 365 days after discharge were 12.28 and 5.59/1,000 person-years (aHR 1.92 [1.30–2.85]) and 7.35 and 2.9/1,000 person-years (aHR 1.98 [1.52–2.58]) for patients discharged with and without acute liver injury, respectively. The incidence rates and aHRs for mortality within 90 days and 365 days after discharge were 82.4 and 27.54/1,000 person-years (aHR 1.73 [1.46–2.05]) and 36.8 and 9.3/1,000 person-years (aHR 1.94 [1.69–2.24]) for patients discharged with and without acute liver injury, respectively. The subgroup analysis of hypoglycemia risk in patients discharged with acute liver injury revealed no significant interaction in risk factors of age, chronic kidney disease, and medications, except for sex difference, which has significant interaction.

CONCLUSIONS

This cohort study demonstrated that patients with T2D and discharged with acute liver injury showed significantly higher risks of severe hypoglycemia and mortality within 90 days and 365 days after discharge than patients discharged with other causes.

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Hypoglycemia blood test

Hypoglycemia is a state of the human body in which the concentration of blood glucose is reduced relative to
normal values. Normally, its level in the blood is approximately 3.5-6.0 mmol / l. Glucose in the body
is formed from carbohydrates supplied with food, as well as during the breakdown of the main reserve substance of the liver –
glycogen. Carbohydrate is an important component that provides the human body with energy, which
essential for the central nervous system (CNS).

Since the brain needs a large amount of energy resources, any decrease in glucose affects
in general condition. Hypoglycemia is manifested by weakness, drowsiness, dizziness, memory loss and
other disorders of brain activity, as well as pallor and clammy sweat. Severe drop in blood sugar
can be manifested by fainting, convulsions and ultimately cause a life-threatening condition –
hypoglycemic coma.

What is hypoglycemia?

Hypoglycemia is classified according to the level of low blood sugar into three degrees of severity – mild,
medium and heavy. For mild hypoglycemia, it is enough to eat or drink a product containing
simple carbohydrates (white sugar). The state changes slightly and is easily corrected. Moderate degree
most often requires outside help, and returning to a normal state will take longer. At
severe degree develops hypoglycemic coma, in which the person is unconscious. Such a state
usually develops at blood glucose levels below 1.5 mmol / l and requires immediate hospitalization in a hospital
to provide medical assistance.

What causes a hypoglycemic state?

There are many causes of hypoglycemia. Conventionally, they can be divided into physiological and pathological. At the same time to
physiological will include starvation, in which there is no intake of a sufficient amount
carbohydrates, strong physical and emotional overstrain, in which the body spends energy
more resources than they receive.

The main pathological conditions in which hypoglycemia occurs include:

1. Diabetes mellitus (DM)

Although diabetes is characterized by elevated glucose levels (hyperglycemia), every patient with
this disease can also face the reverse state. This is due to the fact that glycogen stores in
in the body of a patient with type 1 and type 2 diabetes are greatly reduced, as insulin sensitivity is impaired. In connection with
this, with prolonged fasting and / or an overdose of insulin preparations and other hypoglycemic agents
hypoglycemia occurs. Therefore, patients with diabetes are always advised to carry juice,
or other sugar-containing food.

2. Liver disease

Another cause of low blood glucose levels is liver failure due to various
pathologies – cirrhosis of the liver, alcohol and chemical damage, etc. A normal healthy liver synthesizes from
glycogen coming in a large amount of glucose and stores it. In violation of the functional activity of the liver
carbohydrate storage does not occur and the only source of glucose in the blood is food. Because the
the rhythm of human life does not allow you to always get enough sugars, and the body’s resources are not enough
to close needs, such patients develop hypoglycemic disorders.

3. Problems of the gastrointestinal tract (GIT)

In case of diseases of the gastrointestinal tract and violation of their functions, the absorption of glucose into the blood may decrease, which
leads to insufficient concentration.

4. Congenital pathologies

There are a number of genetic disorders, primarily related to enzymatic activity, in which
the processes of gluconeogenesis (the conversion of glucose from non-carbohydrate compounds) and glycogenolysis (the breakdown of
glycogen to glucose). In such patients, the level of glucose in the blood decreases rapidly and its constant
support.

5. Pathologies of the endocrine glands

Endocrine glands that indirectly (through hormones) affect the level of glucose in the blood include –
pancreas (PG), thyroid (TG), and adrenal glands.

Hypoglycemia may be due to:

• hypothyroidism, in which the level of thyroid hormones is reduced;
• adrenal insufficiency, in which the concentration of cortisol and adrenaline decreases;
• insulinomas – a tumor that produces insulin with increased activity;

6. Renal disorders

Hypoglycemia can be caused by excessive excretion of glucose from the body in the urine due to impaired reabsorption.

7. Severe infectious processes

During infectious processes, a large amount of the body’s energy resources are spent to fight
pathogen, in connection with which hypoglycemia can also occur.

What tests should be done for hypoglycemia?

Hypoglycemia can be diagnosed by the clinical picture and a biochemical blood test. Biochemistry is
the “gold standard” in determining glucose levels. In order to obtain a reliable result, it is necessary
fulfill the following obligatory conditions for venous blood donation:

• blood is donated strictly in the morning on an empty stomach with the last meal 7-8 hours before the examination; do not do it
  eat fatty foods, a large number of sweet carbonated drinks, etc .;
• should avoid stressful situations, both physical and emotional;
• do not drink alcoholic beverages the day before blood donation.

The state of hypoglycemia is observed when the blood glucose concentration drops below 3. 5 mmol/L.

At the same time, the main problem in diagnostics is not the detection of the very fact of the state of hypoglycemia, but
diagnosis of the immediate cause that led to such changes. That is why there is
a range of tests for hypoglycemia that must be passed.

1. Complete blood count

It is worth remembering that a complete blood count should be taken in case of any pathological processes. It reflects
the main blood parameters that can be used to judge the possible presence of a problem. So, changes in leukocyte
formula may indicate the infectious nature of the condition. In addition, a general analysis may help to suspect
pathology, which, although it does not have a direct effect on blood sugar levels, but requires
mandatory treatment in order to avoid serious consequences for the body.

2. Blood chemistry

It was previously said that biochemical analysis helps to directly determine the level of glucose in the blood. However
the study includes not only this indicator, but also many others, allowing to suspect violations
organs and systems of the body. For example, a significant increase in the level of liver enzymes (AST, ALT)
characterizes the destruction of hepatocytes and indicates liver disease requiring further diagnosis.
A decrease in total protein can also be a consequence of a violation of the functional activity of the liver. Level up
creatinine levels suggest impaired renal function, etc.

Glycosylated hemoglobin (HBA1c) is another diagnostic indicator. This connection
which is the glucose-bound hemoglobin in erythrocytes. In healthy people, its level is low.
With a severe increase in blood glucose in diabetes mellitus, the HBA1c level rises strongly and remains high
within 120 days of the last increase. This analysis is carried out with any change in the level of sugar in
blood for a more accurate diagnosis of the condition.

Hypoglycemia, what other tests should be done besides blood?

3. Urinalysis

allows you to evaluate the filtration function, as well as detect / exclude the presence of sugar in the urine. Appearance
carbohydrates in the urine indicates a reabsorption disorder for one reason or another.

4. Examination of hormones of the thyroid gland, adrenal glands, pancreas, pituitary gland

Since all of the above hormones can affect glucose levels, blood levels must be measured
to confirm/deny communication between processes.

5. Additional tests

These include fecal analysis to determine the functions of the digestive system, instrumental
research, primarily ultrasound of the abdominal organs (prostate and liver), kidney research, etc., genetic
analyzes if necessary.

After testing for hypoglycemia, a consultation with a specialist is required to solve the problem and establish
final diagnosis. Be healthy!

Hypoglycemic syndrome in epithelioid hemangioendothelioma of the liver, successful treatment – liver transplantation from a living related donor | Bondar

Hypoglycemic syndrome occurs not only in endocrine diseases; it can complicate the course of many somatic diseases and tumors of pancreatic and extrapancreatic localization. Most often, hypoglycemia develops in patients with mesenchymal tumors and hepatocellular liver cancer – from 4% in North America to 27% in Hong Kong [1]. Hepatocellular cancer is diagnosed in more than 80% of all liver tumors; over the past 20 years, the frequency of this cancer has increased by 62% [2]. The development of hypoglycemia in liver tumors is associated with a decrease in the volume of functioning liver tissue, increased consumption and utilization of glucose by tumor tissue, inhibition of gluconeogenesis and glycogenolysis, and secretion of insulin-like peptides (IGF) [3, 4]. Hypoglycemia in liver tumors is rarely the first symptom of the disease and usually occurs with large tumor sizes and symptoms of tumor intoxication [5].

Epithelioid hemangioendothelioma of the liver is a primary malignant neoplasm from the group of mesenchymal tumors that occurs in less than 1% of cases of all malignant neoplasms of the liver. The frequency is 1 case per 100,000 population per year [6, 7], so the possibilities of studying the clinic of this neoplasm are limited. The clinical course of epithelioid hemangioendothelioma of the liver is highly variable. There are slowly and rapidly progressing variants. The diagnosis is based on the results of histological examination of postoperative material and immunohistochemical examination, which confirm the endothelial structure of the tumor expressing the antigen associated with factor VIII (vWF), CD31 and CD34 [8, 9]. There is no description of hypoglycemia in epithelioid hemangioendothelioma in the literature.

A case report of hypoglycemia as an early symptom of liver epithelioid hemangioendothelioma successfully treated by orthotopic transplantation of a liver fragment from a related donor is presented.

Case description

Patient C ., 35 years old, resident of the Novosibirsk region, was treated in the endocrinology department and the organ transplantation department of the State Budgetary Healthcare Institution of the Novosibirsk Regional Clinical Hospital (SNOKB) (chief physician – A.V. Yudanov ) in June 2016

At admission, he complained of periodic attacks of weakness, trembling, sweating, lethargy and drowsiness. Attacks occurred daily, mainly at night and in the morning. The patient managed and prevented these conditions by frequent intake of sugary foods.

History of life : until the age of 29 he considered himself healthy, worked. After a head injury in 2010, a constant, intense headache and unsteady gait appeared. During examination in the neurosurgical department of the Novosibirsk Research Institute of Traumatology and Orthopedics (NIITO), according to the results of MRI of the brain with contrast, the diagnosis was made: meningioma of the right parietal region with symptoms of initial wedging into the tentorium and foramen magnum. Performed decompression trepanation, partial removal of a giant parasagittal meningioma of the right parietal lobe. Histologically, an atypical meningioma of a mixed structure (angimatous, psammomatous) with signs of active growth. Six months later, the second stage of surgical treatment was performed — complete removal of the meningioma, then a course of radiation therapy, in 2012 — cranioplasty. The patient was examined annually at the NIITO. MRI of the brain in 2016 showed no evidence of tumor recurrence.

Case history : in February 2016, attacks of weakness, fatigue, sweating, body tremors appeared. The patient did not attach importance to changes in his condition, he did not apply to medical institutions. After 2 months, an attack of generalized tonic convulsions first occurred, which were regarded as symptomatic epilepsy after meningioma treatment. The examination revealed hypoglycemia on an empty stomach – 1.4 mmol/l. To clarify the cause of hypoglycemia, he was sent to the endocrinology department of the State Scientific and Clinical Hospital.

On examination, the general condition is satisfactory. The consciousness is clear, the physique is normosthenic. Body temperature 36.6 °C. Body weight 77 kg, height 180 cm, BMI 23 kg/m ² . The skin is of physiological color, moist, clean, turgor and elasticity are preserved. Subcutaneous tissue is expressed moderately, evenly distributed. Lymph nodes are not enlarged. The thyroid gland is not enlarged. NPV 19 in 1 min. Breathing is vesicular, no wheezing. Pulse 78 beats/min, good tension and filling. AD 130/90 mmHg Heart sounds are clear, rhythmic. The tongue is moist and clean. The abdomen is enlarged, soft and painless on palpation. In the right hypochondrium, a tuberous formation is palpated, of a dense consistency, painless, 10 cm in diameter. The liver protrudes from under the costal margin by 5 cm, the size according to Kurlov is 20 × 16 × 14 cm. Intestinal noises are heard clearly. The chair is regular, decorated. The spleen is not palpable. There are no peripheral edema.

Provisional diagnosis : hypoglycemic syndrome of unknown origin. It was necessary to clarify the nature of hypoglycemia – fasting or reactive, with or without an increase in insulin levels. Given the history of surgery for meningioma, it was necessary to exclude secondary chronic adrenal insufficiency, as well as to exclude insulinoma, tumor or metastatic process.

The patient was advised to take fast carbohydrates every 1-2 hours, dexamethasone 4 mg IM was prescribed at night; 40 ml of 40% glucose solution was administered 2-3 times a day during attacks of hypoglycemia. Despite treatment, hypoglycemic conditions occurred up to 2 times a day. Glycemia (according to a glucometer) decreased at night and during the day to 2.0–2.2 mmol/l.

Thrombocytopenia up to 133·10 ⁹ /l was observed in the general blood test, there were no other changes. An increase in the level of gammaglutamyl transpeptidase up to 103.3 U/l, alkaline phosphatase up to 142. 2 U/l, ALT up to 64 U/l was revealed; other indicators are normal: bilirubin 13 µmol/l, total protein 69.5 g/l, urea 2.1 mmol/l, creatinine 59.0 µmol/l, potassium 3.88 mmol/l, sodium 146.2 mmol/l, glycated hemoglobin 4.7%. Insulinoma was ruled out based on low insulin levels — 0.7 µIU/mL (normal 1.9–23.0 µIU/mL) and C-peptide — less than 0.01 ng/mL (normal 0.9–7.1 ng/mL). ml). The content of thyroid hormones and cortisol in plasma is normal, which made it possible to exclude the pathology of the pituitary gland. The level of tumor markers (alpha-fetoprotein 0.0 U/ml, cancer-embryonic antigen 1.79 ng/ml) did not go beyond the normal range. The patient underwent MSCT and MRI of the abdominal organs with contrast, MSCT of the chest.

MSCT of the abdominal cavity organs (Fig. 1) in the liver parenchyma revealed multiple round formations of various sizes (from 2–3 mm in diameter) with uneven, clear contours, the largest have a diameter of 13.2 cm (right lobe) and 13 cm (left lobe), their structure is cystic-solid; in the arterial and venous phases of contrasting, a pronounced uneven accumulation of the contrast agent is noted, a developed vascular network is traced, no other changes in the abdominal organs and retroperitoneal space were detected. Conclusion : voluminous hypervascular formations in the liver parenchyma.

Fig. 1. MSCT of the abdominal cavity: arterial phase (description in the text).

Dynamic MRI with contrast enhancement with gadoxetic acid (Fig. 2) revealed enlarged liver size (vertical size of the right lobe 24 cm, left lobe 18 cm, horizontal 21 cm), the contours are clear, even, with contrast enhancement intact parenchyma increases the density to the maximum in the portal and hepatospecific phases, in Sg7–8 of the liver, a pathological tissue formation of a spherical shape is visualized, with a maximum size of 12 × 13 cm, with uneven large-tuberous contours, heterogeneous in structure, in Sg2–3 a similar pathological tissue formation of a spherical shape is visualized 9×13 cm; both formations maximally intensively accumulate the contrast agent in the arterial phase, numerous spherical foci of various sizes (from 5 to 20 mm in diameter) with clear and even contours, homogeneous in structure, were visualized in the liver parenchyma, no other changes in the abdominal organs and retroperitoneal space were detected. Conclusion : Tomographic findings consistent with hepatocellular carcinoma with multiple bilobar lesions.

Fig. 2. MRI: dynamic scanning of the liver in the axial projection on the LAVABHAsset pulse sequence using gadoxetic acid (description in the text).

MSCT of the chest revealed no distant metastases.

Based on the examination data, the following diagnosis was established: hepatocellular carcinoma in Sg2-3, Sg6-7-8 normal liver with multiple intrahepatic metastases Т4NxM0; severe hypoglycemic syndrome.

Taking into account the young age of the patient, massive bilobar lesion in the absence of signs of dissemination of the process and regional metastasis, as well as localization of the tumor in a normal (cirrhotic) liver, it was decided to use liver transplantation as a treatment option. Due to the risks of implantation metastasis and intra-abdominal bleeding from hypervascularized tumors, preoperative needle biopsy for the purpose of morphological verification of the diagnosis was not performed. Due to the unpredictable time the patient was on the waiting list, a decision was made to use a liver fragment from a related donor. The patient’s uncle was examined as a potential donor.

On 06/07/16, operations were performed on a related couple. The donor operation is a right-sided hemihepatectomy, without any technical features. Brief description of the intervention in the recipient: laparotomy according to the Mercedes type, during the revision of the abdominal cavity, the liver is without signs of cirrhotic changes, significantly enlarged in size, in Sg2-3 and Sg6-7-8 neoplasms of a soft elastic consistency with a diameter of about 13-14 cm each are determined, there is no invasion tumors in the portal gate, retrohepatic segment of the inferior vena cava, in the surrounding tissues and organs, there are no signs of paracaval and paraportal lymphadenopathy, no signs of carcinomatosis and phenomena of portal hypertension. Performed hepatectomy without resection of the retrohepatic segment of the inferior vena cava; the weight of the removed liver was 5 kg (fig. 3, on color insert) . After hepatectomy, transplantation of the right half of the liver from a related donor without any technical features. The operation on the recipient was performed with a constant intravenous infusion of 10% glucose solution; intraoperative blood loss was 1100 ml, the duration of the intervention was 10.5 hours. Immediately after tumor removal, the glucose level returned to normal (5.2–6.7–6.3–5.9 mmol/l).

Fig. 3. View of the removed liver.

Liver without signs of cirrhotic changes, significantly increased in size, in Sg2-3 and Sg6-7-8 neoplasms of soft elastic consistency with a diameter of 13-14 cm each are determined, there is no invasion of the tumor into the portal gate. The weight of the removed liver is 5 kg.

Histological examination of the removed liver : tumor nodes in the liver are represented by proliferation of medium-sized elongated and round-oval cells with spindle-shaped, ovoid and irregularly shaped nuclei, mitotic activity is low, tumor cells grow solidly with the formation of trabeculae and papillary structures, in part fields of view, cavernous cavities, growth of tumor cells in the lumen of sinusoidal vessels, in some preparations, reticulin and collagen fibrosis, infarcts. Conclusion : epithelioid hemangioendothelioma of both lobes of the liver with multifocal growth (2 nodes 13 cm, multiple nodes up to 1 cm), without signs of tumor growth in the edges of the vessels and distant lymph nodes. Immunohistochemical study of (Fig. 4, color insert) revealed active expression of vWF, CD31, CD34, vimentin by tumor cells, cells do not express smooth muscle actin, chromogranin A, CD117. Thus, the histological structure and immunophenotype of the tumor were most consistent with epithelioid hemangioendothelioma of the liver.

Fig. 4. Immunohistochemical study.

Tumor nodules in the liver are represented by proliferation of medium-sized elongated and round-oval cells with fusiform, ovoid and irregularly shaped nuclei, mitotic activity is low. Tumor cells grow both solidly and with the formation of trabeculae and papillary structures; cavernous cavities in part of the visual fields. Growth of tumor cells in the lumen of sinusoidal vessels is noted. Intensive expression of CD34 by the tumor. ×200.

Final clinical diagnosis : epithelioid hemangioendothelioma, multiple bilobar lesion. Severe hypoglycemic syndrome.

The course of the postoperative period was smooth, glycemia varied from 4.2 to 7.6 mmol/l, there were no hypoglycemia. Immunosuppressive therapy was initiated according to the scheme: everolimus de novo ± tacrolimus; a steroid-free protocol was applied (rapid dose reduction of steroids with their complete cancellation on the 5th day).

During 1 year 8 months of follow-up, the patient’s condition is satisfactory, there are no extrahepatic tumors and signs of disease progression. The concentration of everolimus is maintained at the level of 5-7 ng / ml, tacrolimus – 3-5 ng / ml.

Discussion

R. Yeung [5] described two types of hypoglycemia in hepatocellular carcinoma: type A hypoglycemia occurs in poorly differentiated liver tumors, hypoglycemic conditions are mild or moderate in severity and appear 2 weeks before death. Hypoglycemia occurs due to severe liver damage and low glycogen stores. Type B hypoglycemia occurs with slowly growing tumors, is severe and is accompanied by a pronounced impairment of consciousness, convulsions, and is complicated by coma. This type of hypoglycemia is caused by increased synthesis of IGF-2 by the tumor tissue. In rare cases, hypoglycemia is the first manifestation of a liver tumor.

In the present observation, hypoglycemia was an early symptom of a large tumor that significantly replaced the liver parenchyma. At the same time, the patient did not have liver failure, tumor intoxication. The history of the disease in the patient is short, the clinical course of hypoglycemia was initially characterized by bouts of weakness, fatigue, severe sweating, paresthesia, trembling, which were repeated daily and were stopped by easily digestible carbohydrates. After 2 months, hypoglycemia acquired a severe course – the first attack of generalized tonic convulsions occurred, lethargy, inappropriate behavior appeared. After another 1 month, the frequency of seizures increased to 2–4 times a day, which required intravenous administration of a 40% glucose solution and glucocorticoids.

In contrast to insulinoma, patients suffering from fasting hypoglycemia in combination with extrapancreatic tumors are characterized by a decrease in the level of insulin and C-peptide in plasma [10, 11]. The content of insulin and C-peptide in our patient was low. The literature describes clinical cases of hepatocellular liver cancer [12, 13] occurring with hypoglycemia. The pathogenesis of hypoglycemia is associated with increased consumption of glucose by the tumor. There is an inhibition of gluconeogenesis due to the effect on the liver of toxic products secreted by the tumor. The role of cytokines (IL-1, alpha-interferon, TNF-alpha), which are excessively released from the tumor or macrophages activated by the tumor, is not excluded. Increased transport of glucose into the tumor may be mediated by oncogenes that increase the activity of glucose transporters localized within the tumor. Elevated levels of IGF-1 and IGF-2 were diagnosed in 50% of patients with tumors and hypoglycemia. In some patients, IGF-2 and IGF-2-binding protein type 3 are present as a binary complex. This complex reaches target tissues faster, dissociates more easily, leading to an increase in free IGF. In addition, IGF-2 inhibits the secretion of glucagon and growth hormone, which reduces blood glucose levels. IGF-1, like insulin, stimulates glucose uptake by muscle and adipose tissue [14, 15].

The literature describes hypoglycemia in liver cancer, but we did not find a description of epithelioid hemangioendothelioma in combination with hypoglycemia.

Treatment of hypoglycemic syndrome in tumors is usually reduced to the intake of rapidly digestible carbohydrates. Methods of drug therapy are ineffective. An attack of hypoglycemia can be stopped for a short time by intravenous administration of 40–60 ml of a 40% glucose solution. Corticosteroids (dexamethasone 2 mg or prednisolone up to 40 mg daily) are the most commonly used drugs. However, in most cases, only a temporary effect is achieved [5]. According to T. Thipaporn et al. [16], long-acting steroids are more effective. C. Tsai et al. [13] observed a 42-year-old woman with severe hypoglycemia, which was the first manifestation of hepatocellular carcinoma. CT scan of the liver revealed a tumor with a diameter of 15 cm with metastases. Oral intake of easily digestible carbohydrates, administration of glucose solution and prednisolone had no effect. The number of episodes of hypoglycemia was reduced to 1 time per month only after palliative radiotherapy.

In extrapancreatic tumors accompanied by hypoglycemia, the use of diazoxide for preoperative preparation is not indicated, since this drug inhibits the secretion of insulin by pancreatic β-cells. In extrapancreatic tumors, the level of insulin is reduced [17]. The introduction of growth hormone, as well as analogues of somatostatin, glucagon, adrenaline, is not accompanied by a persistent increase in glycemia. The most effective treatment for hypoglycemia caused by a liver tumor is associated with tumor volume reduction using surgical cytoreduction [18, 19], courses of chemotherapy and radiation therapy [20], ethanol injections [1]. With a large tumor volume, liver resection is excluded.

Conclusion

In the presented observation, several methods were used to stop and prevent hypoglycemia: frequent meals (the patient constantly took fast-digesting carbohydrates throughout the day), intravenous administration of 40 ml of 40% glucose solution, intramuscular administration of dexamethasone 2-4 mg / day, prednisolone 30–60 mg/day. However, this treatment only reduced the frequency and severity of hypoglycemia. Due to the large size of the tumor, liver resection was excluded and the only chance to save the patient’s life was liver transplantation. The patient underwent hepatectomy and liver transplantation from a related donor as a radical treatment with a good long-term outcome. Surgical treatment completely eliminated hypoglycemia.

Additional information

Additional materials to the article

Consent of the patient: the patient voluntarily signed an informed consent to the publication of personal medical information in an anonymized form in the journal “Problems of Endocrinology”.

Source of funding: preparation of the article and search and analytical work were carried out at the personal expense of the team of authors.

Conflict of interest: The authors declare no apparent or potential conflicts of interest related to the publication of this article.

Author contributions: all authors were involved in the management of the patient, made a significant contribution to the research and analytical work and preparation of the article, read and approved the final version before publication.

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