Rapid improvement of severe fatty liver in a case of fulminant type 1 diabetes following insulin treatment

Abstract

A 36-year-old woman presented to the emergency room with a consciousness disorder after developing abdominal pain with diarrhea for 2 days. She presented with marked hyperglycemia, ketoacidosis, and increased serum free fatty acid (FFA) levels; however, no elevation in the glycated hemoglobin (HbA1c) levels was observed. Based on the marked depletion of insulin secretion, the patient was diagnosed as diabetic ketoacidosis attributed to fulminant type 1 diabetes (FT1D). Computed tomography on admission revealed severe fatty liver (FL), which improved 17 h following insulin treatment. Insulin treatment also suppressed the serum FFA levels. Some cases of FT1D with FL and liver dysfunction have been reported previously; however, its pathogenesis and clinical course remain unclear. Compared to previous reports, this case reported the shortest time for FL improvement. In this case, rapid and severe insulin deficiency led to a markedly high FFA level and significant accumulation of triglycerides in the hepatocytes, resulting in severe FL. A rapid and large dose of insulin was administered when systemic insulin sensitivity was nearly maximal owing to insulin deficiency, increased insulin efficacy, early reduction of FFA, suppressed triglyceride accumulation in the hepatocytes, and increased triglyceride excretion from the liver. All these factors could have contributed to the rapid improvement in FL.

Introduction

Fulminant type 1 diabetes (FT1D) is defined as diabetes with rapid beta cell destruction, and hyperglycemia and ketoacidosis progression. Notably, 22.6% of FT1D cases are associated with fatty liver (FL) [1]. Here, we report the case of a patient with F1TD with severe FL. Insulin treatment rapidly improved not only the marked hyperglycemia, but also FL within 17 h, as confirmed by computed tomography.

Case presentation

A 36-year-old woman had abdominal pain and diarrhea for 2 days, which was initially diagnosed as viral gastroenteritis; however, the patient lost consciousness and was admitted to our hospital as an emergency. Her blood glucose and urine ketone levels were 919 mg/dL and 3+, respectively. The blood pH, HCO³⁻, and anion gap were 7.175, − 5.3 mEq/L, and 21.9 mEq/L, respectively. The patient was diagnosed with diabetic ketoacidosis and hospitalized.

On admission, her height, weight, body mass index, temperature, blood pressure, pulse, and respiratory rate were 158 cm, 40 kg, 16 kg/m², 37.8 °C, 124/76 mmHg, 92 beats/min, and 14 breaths/min, respectively. She had impaired consciousness, with a Glasgow Coma Scale score of 7 points (eye-opening, 1 point; best verbal response, 2 points; and best motor response, 4 points). Acetone odor and Kussmaul respiration were also observed. Marked dryness of the oral cavity and decreased skin turgor were observed. No abdominal pain was observed. No abnormalities were noted during the physical examination. She had no history of diabetes mellitus.

The laboratory data on admission are presented in Table 1. Despite high blood glucose levels, the glycated hemoglobin (HbA1c) levels were mildly elevated at 7.1%. The insulin secretory capacity, represented by the serum C-peptide (CPR) level, was depleted (0.02 ng/mL). These clinical courses and findings are consistent with those of F1TD.

Table 1.

Laboratory data on admission

Laboratory data
Hematology			Ketone body
WBC	8,550	/μL	Total keton	14,600	μmol/L
RBC	425×104	/μL	Acetoacetic acid	3,530	μmol/L
Hb	12.7	g/dL	β-Hydroxybutyric acid	11,100	μmol/L
Ht	39.1	%	Arterial blood gas analysis (Room air)
Plt	25.6×104	/μL	pH	7.175
Blood chemistry and serology			PaO2	124	mmHg
TP	6.2	g/dL	mEq/L	14.9	mmHg
Alb	3.8	g/dL	mEq/L	5.3	mEq/L
T-Bil	0.5	mg/dL	mg/dL	21.9	mEq/L
ALP	264	U/L	mmHg	2.4	mg/dL
γ-GT	15	U/L	Diabetes related examinations
AST	36	U/L	PG	919	mg/dL
ALT	34	U/L	HbA1c	7.1	%
BUN	59.4	mg/dL	GA	27.5	%
Cr	1.83	mg/dL	Anti-GAD antibody	<5	U/mL
eGFR	26	mL/min	Anti-IA-2 antibody	<0.6	U/mL
UA	14.7	mg/dL	S-CPR	0.02	ng/mL
CK	406	U/L	U-CPR	0.2	μg/day
Amylase	1,128	U/L	Glucagon-loading test (S-CPR calues)
Lipase	41.5	U/L	pre-loading	<0.02	ng/mL
CRP	3.33	mg/dL	post-loading (6min)	<0.02	ng/mL
Na	130	mEq/L	Endocrinology
K	5.4	mEq/L	TSH	0.701	μIU/mL
Cl	96	mEq/L	FT4	0.638	ng/dL
TG	64	mg/dL	FT3	0.62	pg/mL
LDL-C	72	mg/dL	Anti-Tg antibody	<10	U/mL
HDL-C	56	mg/dL	Anti-TPO antibody	<5	U/mL
apo AI	128	mg/dL	HLA
apo AII	18.3	mg/dL	HLA-DR	DR9	DR13
apo B	51	mg/dL	Urinalysis
apo CII	2.8	mg/dL	Protein	1+
apo CIII	11.9	mg/dL	Glucose	4+
apo E	1.6	mg/dL	Ketone	3+
Lp (a)	≦1	mg/dL	Blood	3+
RLP-C	3.3	mg/dL	WBC	–
FFA	1,870	μEq/L	Albumin	175.1	mg/g⋅Cr

WBC white blood cell, RBC red blood cell, Hb hemoglobin, Ht hematocrit, Plt platelet, TP total protein, Alb albumin, T-Bil total bilirubin, ALP alkaline phosphatase, γ-GTP gamma-guanosine triphosphate, AST aspartate aminotransferase, ALT alanine aminotransferase, BUN blood urea nitrogen, Cr creatinine, eGFR estimated glomerular filtration rate, UA uric acid, CK creatine kinase, CRP c-reactive protein, Na sodium, K potassium, Cl chlorine, TG triglyceride, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, apo (AI) apolipoprotein AI, apo (AII) apolipoprotein AII, apo- (B) apolipoprotein B, apo (CII) apolipoprotein CII, apo (CIII) apolipoprotein CIII, apo (E) apolipoprotein E, Lp (a) lipoprotein (a), RLP-C remnant-like particles cholesterol, FFA free fatty acid, pH potential hydrogen, PaO₂ partial pressure of arterial oxygen, PaCO₂ partial pressure of arterial-carbon dioxide, PG plasma glucose, HbA1c glycated hemoglobin; GA glycoalbumin, S-CPR serum C-peptide, U-CPR urinary C-peptide, TSH thyroid stimulating hormone, FT₄ fry thyroxine, FT₃ free- triiodothyronine, Anti-Tg antibody antithyroglobulin antibody, Anti-TPO antibody antithyroid peroxidase antibody, HLA human leukocyte antigen

Serum blood urea nitrogen, creatinine, amylase, and free fatty acid (FFA) levels were elevated. Although the triglyceride levels were not elevated, the apolipoproteins Apo AII, B, and E levels decreased. Abdominal computed tomography (CT) revealed no abnormal findings in the pancreas; however, severe FL with a CT value of 10 Hounsfield units (HU) was observed (Fig. 1a).

Fig. 1.

Clinical course of the patient. Abdominal computed tomography without contrast a before and b 17 h and c 3 days after insulin treatment. d Treatment and changes in the laboratory values. HU, Hounsfield unit. U/h, units per hour; U/day, units per day; cvii, continuous venous insulin infusion; sc, subcutaneous injection; AST, aspartate aminotransferase; ALT, alanine aminotransferase; FFA, free fatty acid; h, hour; d, day

Intravenous saline and insulin infusion improved the hyperglycemia and acidemia after 12 h of treatment (Fig. 1d). After 16 h of treatment, the patient was switched to subcutaneous insulin injections. CT performed 17 h following insulin treatment showed improvement in FL, and further improvement 3 days later. (Fig. 1b, c).

On day 3, the patient was started on a diet and switched to multiple daily injections with insulin Lispro and insulin Degludec (Fig. 1d). The serum aspartate transaminase and alanine transaminase levels peaked on day 3; thereafter, they were nearly normalized by day 25 (Fig. 1d).

The FFA levels were as high as 1870 Eq/L on admission; however, they decreased daily and improved to 395 μEq/L on day 5 (Fig. 1d).

On day 4, a marked increase in the lipase levels was observed (Fig. 1d). CT revealed extension of inflammation in the pararenal space of the anterior kidney, and a diagnosis of acute pancreatitis was formulated. Accordingly, the patient was temporarily switched to continuous venous insulin infusion. Extracellular fluid infusion continued, and ulinastatin was started.

On day 8, enteral nutrition was initiated at 900 kcal/day; the patient was again switched to subcutaneous insulin injections and resumed eating on day 12 and gradually increased to 1,700 kcal/day on day 17. FibroScan performed on day 17 demonstrated liver hardness and liver fat content within normal limits. Insulin doses were increased or decreased during hospitalization and finally the patient was discharged from the hospital with a total insulin dose of 30 units/day (0.75 units/kg of body weight).

Discussion

Nearly 22.6 and 24.4% of the first-episode cases of FT1D and autoimmune type 1 diabetes (AT1D), respectively are complicated by FL, respectively [1]. The mechanism of FL in FT1D is presumably as follows: FFAs resulting from the breakdown of triglycerides in the adipose tissues flow into the liver owing to rapid insulin deficiency, thereby increasing the substrates for triglyceride synthesis in the liver [1]. The patient had no history of obesity or dyslipidemia, and her blood triglyceride and cholesterol levels remained within the normal ranges during hospitalization. Considering the background of the present case, it is unlikely that the patient’s serum FFA levels were high before the onset of FT1D. Most of the serum FFA was likely derived from lipolysis during insulin deficiency.

Notably, insulin treatment rapidly improved FL in this case. Unlike the present case, some cases of T1D/FT1D developed FL and liver dysfunction following insulin supplementation [1, 2]. Insulin stimulates the transcription of the sterol regulatory element-binding protein 1c gene in the liver, which promotes fatty acid synthesis and FL development. In the present case, high-dose insulin was immediately administered when hepatic insulin sensitivity was enhanced owing to rapid and marked insulin depletion. Thus, exogenous insulin may effectively suppress FFA release from the adipose tissues and promote extrahepatic triglyceride release. The effects of insulin may have exceeded those of insulin on fat accumulation in the liver, resulting in rapid FL resolution. How insulin therapy dynamically affects the balance of fat accumulation in the liver of patients with T1D/F1D should be further elucidated.

Additionally, studies using animals with acute insulin depletion by streptozotocin have suggested physiological insulin to be necessary for normal hepatic ApoB gene translation and secretion [3, 4] and that hepatocytes from streptozotocin-induced diabetic rats secrete only one-third of the apo B secreted by hepatocytes from control rats [3]. Decreased Apo B synthesis leads to insufficient very low-density lipoprotein secretion, resulting in decreased extrahepatic triglyceride release [5–7]. These complex changes in lipid metabolism following rapid and severe insulin depletion may have contributed to the FL observed in this case. Low serum ApoB, high FFA, and normal triglyceride levels before insulin treatment in the present case were consistent with this possible pathology. In this case, ApoB and ApoE improved after insulin treatment, but ApoA II remained unchanged.

In the present case, the serum transaminase levels were transiently elevated in the relatively late phase following insulin treatment, despite FL improving liver enzymes peaking 3 days after insulin therapy, and then decreasing and normalizing after 24 days. Nearly 60.4% of the patients with FT1D have reportedly elevated liver enzymes following insulin therapy, which lasts for 20–30 days [1]. Unlike most organs where insulin facilitates glucose entry into cells, excess glucose enters the hepatocytes via insulin-independent passive diffusion. The concomitant presence of insulin activates glycogen synthase, which is a key enzyme involved in glycogen synthesis that converts glucose into glycogen in the hepatocytes. In the presence of both frequent hyperglycemia and supraphysiological insulin levels, glycogen starts accumulating in the hepatocytes [8, 9]. As this cycle continues, hepatomegaly, its associated obstructive symptoms, and the elevation of liver transaminases begins to manifest [8, 10]. Rapid and massive glucose influx into the hepatocytes may cause a transient increase in the serum transaminase levels.

Low free T3 and T4 levels at admission were considered as low T3 syndrome owing to malnutrition, which was unlikely to be associated with FL pathogenesis. Thyroid function improved 3 months after treatment (data not shown).

In conclusion, we report a rare case of FT1D with severe FL that rapidly resolved upon insulin treatment. The clinical course of FT1D should be interpreted taking into consideration the transition in lipid and glucose metabolism from insulin depletion to supplementation.

Data availability

Clinical data from the corresponding author are available upon request.

Declarations

Conflict of interest

The authors state that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human or animal subjects performed by any of the authors.