Type 1 diabetes mellitus in chronic insulin deficiency conditions

Mauriac syndrome is an occasional complication of type 1 diabetes mellitus, which is usually developed in teenagers with poor glycemic control. The true frequency and prevalence of Mauriac syndrome are not known. This is maybe related to the low awareness of clinicians about this clinical condition due to the rather seldom occurrence of this pathological condition. Mauriac syndrome is developed rather sporadically and may occur both in small children and adults [1]. More often, Mauriac syndrome is found in teenagers and young men as teenage is a critical period for patients suffering from type 1 diabetes mellitus [2]. Furthermore, according to the data of Russian and foreign literature, the development of this complication is observed in patients from socially deprived families where, as a rule, there is no adequate control of the child condition [2].

This syndrome is clinically manifested through the retardation of growth and sexual maturation, hepatomegaly. In addition, in patients, one can frequently observe Cushing’s syndrome obesity, an increase in liver enzymes, dyslipidemia in the form of increasing the blood level of cholesterol and triglycerides [3]. The schematic image of a patient with Mauriac syndrome as compared with a typical adult is given in Fig. 1.

Hepatomegaly is a cardinal feature of Mauriac syndrome, which is present in a majority of patients with this complication. It was precisely these changes in glycogenosis type in the liver that had been originally described by Mauriac in 1930 as one of the components of Mauriac syndrome in children with the poor control of type 1 diabetes mellitus [4]. In these patients, hepatomegaly is clinically accompanied by discomfort in the right subcostal region, caused by stretching the liver capsule due to hepatomegaly. It is very often that cases of liver glycogenosis in Mauriac syndrome are interpreted as the non-alcoholic fatty liver disease that is rather complicated to distinguish using the results of anamnesis, physical examination, or laboratory blood analyses [3].

In 2016, McDonald et al. described a potential genetic reason for the development of Mauriac syndrome. In the course of performing the subsequent analysis of genes responsible for glycogen metabolism routes in the liver, a heterozygous mutation of amino acid in the gene of phosphorylase kinase catalytic subunit of gamma-2 (PHKG2) was revealed. This enzyme activates glycogen phosphorylase that catalyzes the initial stage of glycogenolysis. Two interconnected mechanisms are assumed to participate in disease development pathogenesis: the genetic mutation in phosphorylase kinase additionally worsens well-described inhibition of glycogen phosphorylase by hyperglycemia, and this causes errors in the metabolism of glycogen in the liver. So, there is a need to conduct studies on a greater number of patients with liver disease in type 1 diabetes mellitus [5][6].

In the setting of prolonged chronic insulin deficiency and broad daily modulations of blood glucose levels, a decrease in the level of insulin-like growth factor 1 (IFR-1) and the amount of receptors to somatotropic hormone occurs. This results in a relative resistance and insufficient delivery of the growth factor to tissues and organs, leading to growth retardation in the patient. However, the exact etiology has not thus far been determined. Circulating IFR-1 is reduced due to the lack of the stimulating effect of insulin and sex steroids [1][3].

The process of bone tissue growth and chondrocyte differentiation substantially depends on somatotropic hormone and IFR-1. IFR-1 directly stimulates chondrocyte proliferation, and somatotropin, in its turn, enhances local and liver synthesis of IFR-1 that will facilitate chondrocyte growth. With the dysregulation of the somatropin axis (IFR-1) arising in the setting of diabetes mellitus, a decrease in circulating IFR-1, IFR-1 binding protein 3, and somatotropin-binding protein occurs. This is caused by the direct insulin regulation of binding somatotropin with receptors. When conducting insulin therapy, the IFR-1 axis normalization may not be observed. This may be connected with accompanying metabolic changes that lead to growth abnormalities in type 1 diabetes mellitus. In this matter, the patients with diabetes mellitus frequently have an increased level of such circulating inflammatory markers as interleukin-6, C-reactive protein, and fibrinogen. Inflammatory cytokines may influence growth both by a direct effect on the growth plate and by the repression of the IFR-1 action. In diabetes mellitus, the change in nutrient intake to the bone growth zone may be observed and will require a more detailed study [5].

In hyperglycemia, glucose begins to passively enter into hepatocytes through insulin-independent membrane glucose transporter GLUT-2 and rapidly phosphorylate with inhibiting its release from hepatocytes. The insulin injection with its subsequent delivery into blood activates hexokinase and a glucose-hexokinase trap leading to the maximum accumulation of glucose just right in hepatocytes. Then, under glycogen synthase action, the stimulation of synthesizing a large amount of glycogen in the presence of high concentrations of cytoplasmic glucose occurs. The glycogen excess in cells results in liver glycogenosis. The liver malfunction with subsequent failure of hepatocytes leads to the abnormal synthesis of liver aminotransferases, disturbance of the liver synthetic function manifesting by the low albumin level, and increased prothrombin time [1][3][4][7].

Signs of Cushing’s syndrome are probably developed due to secondary hyperadrenocorticism arising from an increase in the serum level of cortisol that responds, as a counter-regulating hormone, to changes in the blood glucose level [3][4].

Mauriac syndrome treatment includes primarily normalizing the patient's glycemic profile. Such an approach is implemented by routine control of daily glycemia using portable glucometers with subsequent adjustment of doses of injectable rapid insulin and injection of supporting doses of prolonged insulin. Continuous delivery of insulin and continuous measurement of the glucose level are a meaningful approach for the treatment of patients with type 1 diabetes mellitus with the purpose of improvement of clinical outcomes [4]. However, one can keep in mind that a dramatic increase in insulin doses may lead to the immediate manifestation of retinopathy or worsening of already existing retinopathy and nephropathy within a month [7].

Modulations of the daily glycemic profile are mostly pronounced in small children, and this is also unfavorable for the development of Mauriac syndrome and other complications of type 1 diabetes mellitus. In this connection, currently, the most appropriate method for conducting insulin replacement therapy is an insulin pump. Continuous infusion of insulin shall be especially considered as a treatment option when intensive insulin therapy and adequate diet with counting bread units become insufficient to stop progressing the liver disease and preventing further complications [1].

Just with inventing continuous insulin therapy, Mauriac syndrome became a rare complication of type 1 diabetes mellitus, as it allows achieving ideal glycemia indicators in young diabetic patients [2].

Clinical Case

The 21-year-old patient Ch., when admitting to the nephrological department of the Kursk Region Clinical Hospital budgetary medical institution, presented problems with pronounced general debility, thirst, oligohydruria, pronounced edema of the face, upper and lower extremities, pain in the epigastric region, diffuse headaches, visual deterioration, sleepiness, and poor appetite.

The patient had been growing in a socially deprived family where there were unfavorable social and material conditions. The patient’s family did not conduct the routine glycemia profile control; the diet with counting bread units was not used; the child was mostly left to his own resources. The patient was seldom followed up by a doctor. Problems with kidneys were revealed in 2012 when the patient was applied domiciliary to the central district hospital with complaints of general debility and frequent headaches. At presentation, an increase in the creatine level up to 220 µmol/L was revealed. An endocrinologist gave recommendations on correction of insulin therapy; a nephrologist prescribed nephron-protective therapy by angiotensin-converting enzyme (ACE) inhibitors. However, the patient did not follow medical advice to a full extent.

From 16 years of age, he began to notice the growth retardation as compared with children of the same age; there were no signs of a male pattern of hair distribution (no hair growth on face and armpits) and libido. However, from this age and till now, the patient had not been applied for medical advice (there were no data of a medical examination in the patient’s ambulatory medical record).

Substantial worsening of the state was observed after 5 years when general debility and thirst began to increase; the hyperglycemia of 30 mmol/L was verified, due to which the patient was delivered by an emergency medical service team to the Kursk Regional Clinical Hospital.

Physical findings were the following: general condition was of moderate severity, appearance did not correspond to the age, the patient looked like a 15-year-old person. The height was 148 cm, the weight was 55 kg, BMI was 25.1 kg/m². The color of skin and visual mucous membranes was pale, bile-stained. The skin elasticity was reduced. The skin was dry. There were no signs of a male pattern of hair distribution. The subcutaneous adipose tissue was developed irregularly with the maximum deposits in facial and abdominal regions. There were observed blepharedema, extremities edema, and skin pitting edema. The heart boundaries were widened to the left. Heart rate = Ps = 90 per min. The heart sounds were thudding. Blood pressure (BP) was 140/90 mm Hg. The tongue was coated. The abdomen was soft. The liver was not extruded from under the edge of the costal arch. Tinel’s sign was negative from both sides. The patient did have a sexual experience.

Due to national peculiarities, the patient’s family was against photography.

When analyzing the laboratory data, the signs of carbohydrate metabolism decompensation and progressing chronic disease of the kidneys were revealed.

• microcytic hypochromic anemia: hematocrit of 18%, hemoglobin of 61 g/L, erythrocytes of 2.3·10¹² /L, the globular value of 0.8, MCH of 26.1 pg, MCV of 78.2 fL, ESR of 17 mm/h;

• hyperglycemia: blood glucose of 24.6 mmol/L;
• biochemical blood analysis: hyperazotemia – urea of 36.6 mmol/L, creatinine of 1030.8 µmol/L; hypoproteinemia – total protein of 49.1 g/L; the blood serum indicators of aminotransferases and electrolytes were within normal limits. An insignificant increase in cardiac-specific enzymes: CPK-MB of 59.7 U/L, troponin T of 0.158 ng/L.

In the overall uranalysis, the following changes were observed: urine concentration of 1004; clarity – turbid; proteinuria – protein of 1.12 g/L; leukocyturia – leukocytes of 13–18 V.f., renal epithelium 1–2 V.f.

When counting the glomerular filtration rate by the Cockcroft-Gault formula, the indicator was 7.76 mL/min corresponding to terminal renal impairment with the necessity of replacement therapy.

When admitting, in the course of abdominal and renal sonography, diffuse changes in the hepatic parenchyma were revealed (increased echogenicity, small-grained and medium-grained, regular ultrasonic texture). The liver was not extruded from under the edge of the costal arch. The oblique measurement was 16.7 cm; the craniocaudal measurement was 8.4 cm. The hepatic ducts were not enlarged. The choledochus was 0.6 cm. The cholecystitis was within the normal limits. The pancreas was not enlarged; the echogenicity was increased. The major pancreatic duct was not enlarged. The lien had S = 22 cm² and was without a local pathology. The kidneys were characterized: the right 93 × 49, parenchyma t(m) of 13 mm; the left 89 × 44 mm, parenchyma t(m) of 12 mm. Urinary stasis was not observed. There were pronounced diffuse changes in the parenchyma of both kidneys (increased echogenicity, accentuated pyramids). In the abdominal cavity, free fluid was observed (subhepatically, in the parasplenic area, and lesser pelvis) with a total volume of about 2 L.

The bladder sonography: the bladder had a conventional shape. Its volume was about 100 mL, the walls were irregularly enlarged, 6 mm. The content was a homogenous suspension in the lumen.

The judgment based on the results of the electrocardiogram was the following: sinus regular rhythm. RR was 0.76, heart rate was 79/min, PQ was 0.16. There were dystrophic disturbances in the myocardium. The final ventricular deflection was negative in the V3 – V6 derivations.

Echocardiography: the C₁B aorta diameter was 2.3 (N 2.0–3.7). The aorta walls were condensed. The aortic valve cusps were not changed; the opening was 1.4; P_∆av was 10 mm Hg. The size of the left atrium was 3.7 (N 1.8–3.6). The mitral valve cusps were not changed. The mitral valve cusps movement was discordant, diphasic. The left ventricular chamber dimension at the end diastole was 4.0 (N up to 5.4); the end-systolic dimension was 2.6 (N up to 4.04); the left ventricular ejection fraction was 64% (N 60–70%). The interventricular septum thickness was 1.2–1.3 (N up to 0.84). The interventricular septum movement was within the normal limits. The diastolic left ventricular posterior wall was 1.2 (N 0.7–1.1). The right ventricular chamber dimension was 4.0 (N up to 5.4). The right atrium dimension was 3.6 ´ 4.2. The left ventricular contractility failures were not revealed. The left ventricular diastolic function was not impaired. There was no fluid in the cavity of the pericardium. Doppler echocardiography showed regurgitation. Tricuspid valve (+; ++), mitral valve (+). The average pressure in the pulmonary artery was 12.0 mm Hg. Judgment: aortic root concretion, non-pronounced tricuspid failure, non-pronounced hypertrophy of the left ventricular myocardium.

The patient was advised by a urologist, a neurogenic dysfunction of the bladder of hypotonic type with acute retention of urine was revealed. In this connection, the urethral Foley catheter was installed.

Discussion

In patient Ch., the following clinical and anamnestic data, as well as the investigations that permit to diagnose Mauriac syndrome, were observed:

• short stature;
• signs of sexual infantilism: the lack of a male pattern of hair distribution and libido;
• Cushing’s distribution pattern of the subcutaneous adipose tissue;
• hepatomegaly based on the abdominal sonography.

Following the complex examination by a nephrologist together with endocrinologists, the patient was diagnosed with: type 1 diabetes mellitus in a severe clinical course, decompensation. Mauriac syndrome. Ketonuria. Diabetic nephropathy, chronic kidney disease stage 5, progression. Renal anemia. Diabetic autonomic cardiovascular neuropathy. Stage III symptomatic arterial hypertension, right ventricular myocardial hypertrophy, risk 4, CHF I, FC III.

Due to GFR of below 10 mL/min, an increase in creatinine above 0.6 mmol/L, the presence of pronounced intoxication syndrome, the patient had received renal replacement therapy and ketoacidosis correction. For the correction of chronic anemia, hemotransfusion of packed erythrocytes was conducted in a volume of 259 mL.

For the treatment of the underlying disease, the patient had received rapid insulin with due regard to indicators of glycemic profile 3 times per day in a dose of 6–8 U and insulin glargine in a dose of 12–14 U.

For the treatment of accompanying cardiac pathology, the patient was advised to take antiaggregants, ACE inhibitors, statins, and beta-blockers.

During the second hemodialysis session, BP was noted to increase up to 180/100 mm Hg jugulated by taking captopril.

In the setting of the conducted treatment, positive dynamics were observed in the patient: activating the patient, reducing intoxication and edema syndrome. BP decreased to 130/80 mm Hg. The native diuresis of up to 600 mL/day was developed.

Conclusion

At present, Mauriac syndrome occurs rather seldom. This fact is directly connected with an ability to inculcate to a patient and his family a need for routine dynamic observation following medical advice on routine complex insulin therapy in patients of infantile age with type 1 diabetes mellitus.

Such a clinical case indicates that, in the course of diabetes mellitus and development of complications in a child, non-observance of medical advice on diet therapy with counting bread units, lack of routine control of the patient’s glycemic profile are of great significance. This causes the insufficiency of the replacement function of insulin therapy, leading to multiple polysystemic lesions of organs and tissues, which, as a rule, poorly respond to treatment and substantially worsen the quality of the patient’s life.