Glycogenic hepatopathy: A narrative review

Table 1 Summary of the major case reports in English (pub med indexed) on Glycogenic hepatopathy in type 1 diabetes mellitus

Ref.	Study design	Age/sex	HbA1C	Keto acidosis	Hepatomegaly	AST/ALT/ALP/T bili	Normalization of LFTs
Ruschhaupt et al[1], 1970	Case report	13/M	NA	Yes	Yes	9/14/115/128/NA	5 d
Berman et al[2], 1973	Case report	21/F	NA	Yes	Yes	UK	Expired (5 d)
Olsson et al[3], 1989	Case report	15/F	NA	Yes	Yes	535/417/570/NA	10 d
		20/F	NA	No	Yes	1117/1235/941/NA	18 mo
		24/F	NA	Yes	No	323/276/429/NA	NA
Munns et al[4], 2000	Case reports	13/M	14.1	No	Yes	132/135/170/NA	4 wk
		17/F	13.3	No	Yes	102/147/175/NA	2 wk
		16/F	12.2	No	Yes	567/316/196/NA	2 wk
Fridell et al[5], 2007	Case report	18/F	NA	Yes	Yes	Elevated/N	After pancreatic transplant
		21/M	NA	No	Yes	Elevated/N	After pancreatic transplant
Cuthbertson et al[6], 2007	Case report	19/F	12.2	Yes	Yes	NA/800/132/N	NA
Sayuk et al[7], 2007	Case report	19/F	8.1	Yes	Yes	98/49/147/0.5	NA
		37/M	16.0	Yes	Yes	226/399/326/0.9	NA
Bassett et al[8], 2008	Case report	10/F	10.1	No	No	143/147/137/N	NA
Abaci et al[9], 2008	Case report	16/M	11.1	No	Yes	66/58/431/0.8	3 mo
Hudacko et al[10], 2008	Case report	20/F	13.3	No	Yes	249/383/NA/NA	5 mo
Sweetser et al[11], 2010	Case report	27/M	15.0	No	Yes	6720/2549/529/1.7	3 mo
Van Den Brand[12], 2009	Case report	29/F	15.3	No	No	2500/1000/316/NA	NA
Saxena et al[13], 2010	Case report	33/F	13.7	No	No	428/404/205/N	12 mo
Bua et al[14], 2010	Case report	17/F	12.0	No	Yes	138/164/NA/NA	12 mo
Aljabri et al[15], 2011	Case report	13/F	13.0	No	Yes	NA/500/137/N	3 mo
Dantuluri et al[16], 2012	Case report	14/F	11.0	No	Yes	Elevated	Few days
Lin et al[17], 2012	Case report	10/ F	12.8	Yes	Yes	121/194/185/NA	6 mo
Messeri et al[18], 2012	Case report	31/F	10.3	No	Yes	225/258/375/0.54	2 mo
Murata et al[19], 2012	Case report	21/M	6.2	Yes	No	119/122/NA/NA	25 d
Cha et al[20], 2012	Case report	22/F	13.8	No	Yes	1028/365/346/0.5	8 wk
		26/F	12.9	Yes	Yes	914/307/189/0.5	4 wk
		20/F	13.6	No	No	1310/346/132/0.2	16 wk
Saadi T[21], 2012	Case report	18/M	11.0	No	Yes	144/92/123/1.4	3 mo
Saikusa et al[22], 2012	Case report	13/M	12.0	No	Yes	100/191/NA/NA	NA
Imtiaz et al[23], 2013	Case report	19/F	14.6	Yes	Yes	NA/199/139/NA	5 mo
Butts et al[24], 2014	Case report	13/F	8.8	Yes	Yes	NA/113/NA/NA	NA
Jeong et al[25], 2014	Case report	13/F	10.7	Yes	Yes	105/84/NA/NA	3 mo
Martin et al[26], 2014	Case report	13/M	10.4	Yes	Yes	3969/1196/NA/NA	16 d
Parmar et al[27], 2015	Case report	21/F	NA	Yes	Yes	4202/973/N/N	1 wk
Xu et al[28], 2015	Case report	22/M	14.6	No	Yes	331/223/223/0.3	NA
Garcia-Suarez et al[29], 2015	Case report	28/F	10.5	No	Yes	1600/534/N/N	NA
Atmaca et al[30], 2015	Case report	19/M	NA	Yes	Yes	603/570/921/NA	3 wk
Irani et al[31], 2015	Case report	19/M	12.0	Yes	Yes	505/345/145/N	NA
Brouwers et al[32], 2015	Case report	19/F	9.5	No	Yes	Elevated	NA
		19/F	13.3	No	Yes	Elevated	NA
		17/M	12.7	No	Yes	Elevated	NA
		20/F	14.7	No	Yes	Elevated	NA
Charndrasekaran et al[33], 2015	Case report	5/F	16.1	Yes	Yes	53/20/NA/0.7	NA
Silva et al[34], 2016	Case report	21/F	9.0	Yes	Yes	110/120/190/0.74	Few days
		20/F	10.1	Yes	Yes	270/423/179/1	Few days
		29/F	10.9	No	Yes	910/461/172/0.35	3 mo
		22/M	15.7	Yes	Yes	226/109/79/0.64	2 wk
Deemer et al[35], 2016	Case report	18/F	11.3	Yes	Yes	NA/36/120/N	NA
Saracho et al[36], 2016	Case report	14/M	12.8	Yes	Yes	Elevated	NA
Chandel et al[37], 2017	Case report	12/F	10.5	Yes	Yes	690/356/158/0.2	3 mo
Ikarashi et al[38], 2017	Case report	21/M	11.7	No	Yes	2723/956/NA/NA	1 mo
		24/F	11.0	Yes	Yes	658/216/NA/NA	Few days
		19/F	13.6	Yes	Yes	737/266/NA/NA	Few days
		29/F	16.5	Yes	Yes	469/243/NA/NA	6 mo
Maharaj et al[39], 2017	Case report	23/F	12.3	Yes	Yes	127/199/160/2.7	Few days
Al Sarkhy et al[40], 2017	Case report	6/M	11.6	Yes	Yes	367/205/221/N	Few days
Shah et al[41], 2017	Case report	31/F	NA	Yes	Yes	627/185/280/0.7	NA
Omer[42], 2017	Case report	14/M	11.0	Yes	Yes	Normal	NA

HbA1C: Hemoglobin A1c; AST: Aspartate transferase; ALT: Alanine transferase; ALP: Alkaline phosphatase; T bili: Total bilirubin; M: Male; F: Female; NA: Not available.

Table 2 Summary of the major studies in English (pub med indexed) on Glycogenic hepatopathy in type 1 diabetes mellitus

Ref.	Study design	Age/sex	HbA1C	Keto acidosis	Hepatomegaly	Liver abnormality	Normalization of LFTs
Chatila et al[43], 1996	Retrospective Study	Mild Fibrosis (14%)	11patients (8-A and 3-P)
		41/F	NA	NA	No	20/45/1.4 x ULN/0.35	Few days to weeks
		21/F	NA	NA	No	282/404/0.4 x ULN/0.28	Few days to weeks
		58/F	NA	NA	Yes	35/56/3.2 x ULN/0.40	Few days to weeks
		70/F	NA	NA	Yes	76/NA/NA/1.28	Few days to weeks
		36/F	NA	NA	No	40/86/2.1 x ULN/0.28	Few days to weeks
		46/F	NA	NA	Yes	22/20/1.7 x ULN/N	Few days to weeks
		23/F	NA	NA	Yes	265/410/9.5 x ULN/0.40	Few days to weeks
		19/F	NA	NA	Yes	344/532/2.6 x ULN/0.8	Few days to weeks
		13/M	NA	NA	Yes	940/910/2 x ULN/0.30	Few days to weeks
		13/M	NA	NA	Yes	85/NA/0.3 x ULN/0.48	Few days to weeks
		15/M	NA	NA	Yes	NA/NA/1.9 x ULN/0.08	Few days to weeks
Torbenson et al[44], 2006	Retrospective Study	14 patients
		19/F	NA	Yes	Yes	97/83/80/NA	NA
		1/2M	13.5	Yes	Yes	49/47/182/NA	NA
		22/F	NA	No	Yes	48/77/62/NA	NA
		8/M	NA	No	Yes	Elevated/NA	NA
		15/F	NA	No	NA	Normal	NA
		22/M	16	Yes	Yes	1100/360/251/NA	NA
		25/M	10.8	NA	NA	1629/1128/298/NA	NA
		16/M	NA	Yes	NA	Elevated/NA	NA
		20/M	9.9	No	yes	N/120/147/NA	NA
		18/F	10.8	No	NA	N/57/N/NA	NA
		28/M	NA	No	NA	1099/1544/384/NA	NA
		34/M	10.1	No	Yes	N/NA/N/NA	NA
		16/M	NA	No	Yes	1413/1354/476/NA	NA
		23/F	NA	No	Yes	255/224/307/NA	NA
Fitzpatrick et al[45], 2014	Retrospective	31 patients	11(Mean)	Yes-all	76/76/NA/NA(M)	NA	14 (73%) Fibrosis
		16M/15F	12Mild and 2Bridging
		Median age 15	Fibrosis
Mukewar et al[46], 2017	Case control study	20 patients	11.4(Mean) 55%	88.90%	301/308/170/0.5(M)	8 mo	10% Mild fibrosis but no bridging fibrosis
		16F/4M
		24-A, 12-P

T1DM: Type 1 diabetes mellitus; HbA1C: Hemoglobin A1c; AST: Aspartate transferase; ALT: Alanine transferase; ALP: Alkaline phosphatase; T bili: Total bilirubin; M: Male; F: Female; NA: Not available; A: Adults; P: Pediatrics.

Table 3 Summary of the major case reports in English (PubMed indexed) on Glycogenic hepatopathy in type 2 diabetes mellitus

Ref.	Study design	Age/sex	Type of DM/insulin	A1C	Keto acidosis	Hepatomegaly	AST/ALT/ALP/T bili	normalization fibrosis of LFTs
Olson et al[3], 1989	Case report	39/M	Type 2/insulin	NA	Yes	No	429/764/1882/NA	21 d
Tsujimoto et al[47], 2006	Case report	41/M	Type 2/insulin	10	No	Yes	1064/1024/202/2.3	17 d
Umpaichitra[48], 2016	Case report	15/M	T2DM/metformin	6.5	No	Yes	245/330/N/N	18 mo

T2DM: Type 2 diabetes mellitus; HbA1C: Hemoglobin A1c; AST; Aspartate transferase; ALT: Alanine transferase; ALP: Alkaline phosphatase; T bili: Total bilirubin; M: Male; F: Female; NA: Not available.

Table 4 Summary of the published articles in English (PubMed indexed) on Glycogenic hepatopathy without DM

Ref.	Pathology	Study design	Age/sex	Hepatomegaly	AST/ALT/ALP/ T bili	Normalization	Fibrosis of LFTs
Resnick et al[56], 2011	Dumping syndrome	Case report	2/M	No	NA/199/NA/NA	16 mo	No fibrosis
Kransdorf et al[57], 2015	Anorexia nervosa	Case report	26/F	NA	75/101/108/	NA	No fibrosis
Iancu et al[58], 1986	Steroids use	Retrospective	6 mo-14 yr	Yes	Normal	3-5 d	No fibrosis

AST: Aspartate transferase; ALP: Alanine transferase; ALT: Alkaline phosphatase; T bili: Total bilirubin; M: Male; F: Female; NA: Not available.

Table 5 Summery of the main differential diagnosis for glycogenic hepatopathy

	Main etiology	Clinical presentation	Imaging characteristics	Key, liver biopsy pathological features	Diagnosis	Management	Cirrhosis
GH	Acquired excessive glycogen deposition in the liver mostly seen in patients with T1DM	Hyperglycemia with hyperglycemic symptoms; could be asymptomatic. Liver enzyme elevation is mild to extreme range in some case	US and CT shows increased echogenicity. Dual-Echo MRI; iso-intense between the in-phase and out-of-phase images, and low intensity on subtraction	Glycogen deposition in the cytoplasm with swollen hepatocytes, with or without mild steatosis and fibrosis. Diastase digestion of glycogen cause hepatocytes to turn into “ghost cells”	Radiologic and liver biopsy	Optimal control of DM	May have mild fibrosis, severe fibrosis is very rare and seen in only a few reported cases
GSD	Inborn errors of glucose and glycogen metabolism results in abnormal deposition of glycogen	Presentation varies depend on types of GSDs They will have manifestations of a liver, kidney, and skeletal muscle involvement with hypoglycemia, hepatomegaly, muscle cramps, and weakness, etc	Like GH	Findings vary in different type of GSDs; Nonspecific histologic findings to PAS positive glycogen deposition which could be diastase sensitive or resistant	Biochemical tests and molecular testing	Symptomatic treatment to dietary changes to maintain the blood glucose level and pharmacologic therapy in different types of GSDs. May need liver transplantation in selected cases	Some GSD can progress to cirrhosis
NAFLD	Hepatic steatosis	Most patients asymptomatic and some may have minor symptoms, Liver enzymes elevation usually < 5 times upper limit of normal	US and CT shows increased echogenicity. Dual-Echo MRI; low intensity on the in-phase image, and high intensity on the out-of-phase image and high intensity on subtraction.	Steatosis with or without lobular inflammation and hepatocyte ballooning. May have varying degrees of fibrosis	Radiologic and liver biopsy	Lifestyle modification and pharmacologic therapies. May need liver transplant in advanced cirrhosis	Can progress to cirrhosis
Hepatosclerosis	Is a hepatic manifestation of microangiopathic disease seen in long -standing DM	Often clinically silent, Serum aminotransferases are normal or minimally elevated. ALP, Total bilirubin may be elevated	No specific imaging characteristics	Extensive dense perisinusoidal fibrosis	Liver biopsy	Unknown	Unknown
AIH	Chronic Hepatitis of unknown etiology	Spectrum of clinical manifestations ranges from asymptomatic patients to those with considerable symptoms, and rarely presents with acute liver failure	No characteristic imaging features, may show cirrhotic liver in advance case	Interface hepatitis and portal lymphoplasmacytic infiltrate with varying degree of fibrosis	Characteristic biochemical tests and liver biopsy	Glucocorticoid monotherapy or in combination with immunomodulators. Rarely may require liver transplantation	Can progress to cirrhosis
Hemochromatosis	Autosomal recessive disorder. Mutations cause increased iron absorption and excessive deposition in the liver, heart, pancreas, and pituitary	Asymptomatic or chronic liver disease with elevated transaminases, skin pigmentation, DM, arthropathy, impotence and cardiac enlargement, etc	MRI is most sensitive and can estimate iron concentration in the liver. Dual-Echo MRI; demonstrates decreased signal intensity in the affected tissues on the in-phase images compared with the out of- phase images (opposite of steatosis)	A liver biopsy will reveal iron overload. Presence of cirrhosis can be determined	Biochemical tests including genetic testing, radiologic, and liver biopsy	Phlebotomy or Chelation therapy if unable to tolerate phlebotomy	Can progress to cirrhosis
Wilson disease	Autosomal recessive disorder with impaired cellular copper transport and impaired biliary copper excretion results in accumulation of copper most notably the liver, brain, and cornea.	Predominantly hepatic, neurologic, and psychiatric manifestations. Elevated transaminases mild to moderate and ALP may be markedly subnormal	US, CT, may show signs of cirrhosis and normal caudate lobe which is contrary to other types cirrhosis	Vary largely from fatty changes to cirrhosis and occasionally fulminant hepatic necrosis. Can be stained for copper	Biochemical tests and slit lamp examination with or without genetic testing and liver biopsy	Treatment with a chelating agent. Some cases may require liver transplantation	Can progress to cirrhosis
Acute viral hepatitis A, B, C, D and E. Rarely, HSV, VZ, EBV and CMV	Hepatitis A and E are transmitted by feco- oral route; Rest of the viruses spread either by sexual contact, contact with body fluids or blood or from birth from an infected mother	Many of the symptoms are nonspecific; May have marked elevation in transaminases often > 15 times the normal	US or CT findings are nonspecific; Could be used to rule out other causes	Liver biopsy shows hepatocyte necrosis with a portal, periportal and lobular lymphocytic infiltration; Plasma cells present during resolving phase	Diagnosis by biochemical tests	Treatment conservative or antiviral therapy	Acute infection may progress to chronic, and that may progress to cirrhosis

PAS: Periodic-acid Schiff; T1DM: Type 1 diabetes mellitus; US: Ultrasound; CT: Computed tomography; GH: Glycogenic hepatopathy; GSD: Glycogen storage disease; NAFLD: Non-alcoholic fatty liver disease; AIH: Auto immune hepatitis; DM: Diabetes mellitus; ALP: Alkaline phosphatase; HSV: Herpes simplex virus; VZ: Varicella zoster virus; CMV; Cytomegalovirus.