Hepatogenous diabetes: Knowledge, evidence, and skepticism

Table 1 Characteristics of diabetes in patients with cirrhosis that favour a diagnosis of hepatogenous diabetes over type-2 diabetes mellitus

Following characteristics favour a diagnosis of HD
Occurrence after the onset of liver cirrhosis
Low prevalence of metabolic risk factors1 or a family history of DM
Normal fasting glycemia but abnormal oral glucose tolerance test
Low prevalence of microvascular complications, such as diabetic retinopathy
Associated with higher levels of hyperinsulinemia, insulin resistance, and an increased risk of hypoglycemia due to high glycemic variability
Higher association with the severity of liver cirrhosis and liver related complications
Remission after a liver transplantation

¹Obesity, hyperlipidemia.

HD: Hepatogenous diabetes; T2DM: Type-2 diabetes mellitus.

Table 2 Reported prevalence rates of hepatogenous diabetes in patients with liver cirrhosis

Ref.	Patients (n)	Diagnostic method	HD, n (%)	IGT, n (%)
Holstein et al[31]	35	OGTT	20 (57)	13 (37)
Tietge et al[114]	100	OGTT	35 (35)1	38 (38)
Nishida et al[25]	46	OGTT	21 (38)1	13 (23)
García-Compeán et al[30]	130	OGTT	28 (21.5)	36 (38.5)
Jeon et al[29]	195	OGTT	108 (55.4)	169 (86.7)
Ramachandran et al[23]	202	Clinical history2	59 (29.2)	NS
Wang et al[22]	207	Clinical history2	33 (15.97)	NS
Vasepalli et al[28]	121	OGTT	52 (42.9)	58 (47.9)

¹Likely hepatogenous diabetes (diabetes diagnosed after oral glucose tolerance test in non-diabetic cirrhosis).

²Onset of diabetes after diagnosis of cirrhosis.

HD: Hepatogenous diabetes; LC: Liver cirrhosis; IGT: Impaired glucose tolerance; OGTT: Oral glucose tolerance test; NS: Not stated.

Table 3 Studies depicting clinical impact of diabetes mellitus/hepatogenous diabetes in patients with liver cirrhosis

Ref.	Design	n	Main outcomes/remarks
Bianchi et al[112]	Retro-prospective	354	5 yr survival: 41% with DM and 56% without DM (P = 0.005)
Holstein et al[31]	Prospective cohort	52	51% of HD patients died within median of 5.7 yr after diagnosis of DM. Remark: No data on non-diabetic control
Moreau et al[136]	Prospective cohort	75	Survival in patients with and without DM: 18% and 58%, respectively
Sigal et al[97]	Cross-sectional	65	Incidence and severity of HE was higher in diabetics and DM was an independent risk factor for HE (P = 0.0008). Remark: study involved only HCV cirrhosis
Nishida et al[25]	Prospective cohort	56	5 yr survival was 94%, 68% and 56%, with NGT, IGT and DM, respectively
Tietge et al[114]	Case-control study	100	Pre-transplant IGT or DM was risk factor for post-LT DM. Remark: Only 31 patients were prospectively evaluated
Jeon et al[29]	Prospective cohort	195	HD correlated significantly with HVPG and VH. Post-prandial hyperglycemia correlation with risk of VH in 6 mo
García-Compeán et al[113]	Prospective cohort	100	5 yr cumulated survival was lower in IGT patients than NGT (31.7% vs 71.6%, P = 0.02)
Elkrief et al[106]	Retrospective cohort	348	DM was independently associated with ascites, infections, HE, HCC and mortality. Remarks: Only HCV cirrhosis studied
Yang et al[104]	Prospective cohort	146	DM was among independent predictors of VH (OR = 4.90)
Jepsen et al[98]	Database analysis	863	Diabetic patients had a higher episode of first-time overt HE and HE progression beyond grade 2 than non-diabetics. Remarks: Original trials used vaptan which could be a confounder
Khafaga et al[137]	Prospective case-control	60	Proportion of VH (46.4% vs 10%), HE (36% vs 10%) and mortality (16.6% vs 6.7%) was higher among diabetics compared to non-diabetic LC
Qi et al[105]	Retrospective	145	In-hospital mortality was 20.6% in diabetics and 4.3% in nondiabetics (P = 0.003)
Hoehn et al[116]	Retrospective	12442	Diabetic recipients had longer hospitalization (10 vs 9 d) and higher peri-transplant mortality (5% vs 4%)
Yang et al[110]	Retrospective cohort	739	DM increased the risk of HCC in non-HCV cirrhosis (HR = 2.1)
Routhu et al[100]	Retrospective cohort	895	DM was an independent predictor of HE
Ramachandran et al[23]	Prospective cohort	222	HD patients had higher incidence of gall stones (27% vs 13%) and urinary infection (28% vs 7%), compared to those without DM
Tergast et al[108]	Prospective	475	DM patients had an increased risk for SBP (HR = 1.51), especially when HbA1c values ≥ 6.4%
Wang et al[22]	Retrospective	207	Rebleeding rate following variceal endotherapy was higher (approximately 5 times) in diabetics, including HD, than non-diabetics at 1, 3, and 6 mo
Rosenblatt et al[109]	Retrospective (National database)	906559	Uncontrolled DM was associated with an increased risk of bacterial infection (OR = 1.33) and death (OR = 1.62)
Labenz et al[138]	Prospective cohort s	240	DM was independently associated with covert HE. The risk of HE and overt HE was more pronounced when HbA1c ≥ 6.5%

DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HCV: Hepatis C virus; HD: Hepatogenous diabetes; HE: Hepatic encephalopathy; HR: Hazard ratio; IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; OR: Odds ratio; VH: Variceal hemorrhage.

Table 4 Factors that might influence selection of antidiabetic medication for hepatogenous diabetes

Condition	Antidiabetic drug with pros and cons	Preferences
Obesity	Metformin, SGLT2i, and GLP-1 agonists promote weight loss; DPP-4 inhibitors are weight neutral; Sulfonylureas, Pioglitazone, and Insulin promote weight gain	Should be preferred; May be considered; Consider alternative
Sarcopenia	Metformin and TZD appears to have favorable effect on muscles mass; SGLT2 inhibitors, SUs (especially glibenclamide and glinides) may increase the risk of sarcopenia	Should be preferred; Consider alternative
Hyperammonemia/Recurrent HE	Metformin and AGIs cause reduction of blood ammonia levels and risk of HE	May be preferred
Renal impairment	Insulin and linagliptin appear to be safe; SGLT-2 inhibitors may be considered with dose modification. It has added diuretic advantage; Metformin increases the risk of lactic acidosis	Should be preferred; May be considered; Should be avoided
Hypoglycemia	Insulin in SU have high risk of hypoglycaemia; Metformin, PZD, DPP4i and SGLT2 inhibitors have low risk of hypoglycaemia	Should be avoided; May be considered
LC with dysplastic liver lesion/high serum AFP	Metformin decreases the risk of HCC; DPP4 inhibitors and pioglitazone inhibit HCC development in experimental model; Insulin increases risk of HCC	Should be preferred; May be consider; Should be avoided

TZD: Thiazolidinedione; SU: Sulfonylurea; GLP-1: Glucagon-like peptide-1; DPP-4: Dipeptidyl peptidase 4; AGI: Alpha-glucosidase inhibitors; SGLT2: Sodium glucose co-transporter-2; HE: Hepatic encephalopathy; HCC: Hepatocellular carcinoma; AFP: Alfa-fetoprotein.