Is liver disease a threat to patients with metabolic disorders?

Figures & data

Table I. Liver disease‐related mortality associated with metabolic disorders.

First author (ref)	Area	Population	Result	Comment
Sasaki 64	Japan (Osaka prefecture)	Population‐based study on 32,222 death certificates of patients with diabetes; observation period, 30 years	Death rate for liver cirrhosis increases from 2.1% in the period 1960–64 to 4.6% in 1985–89.	No data on other risk factors for liver disease in the population.
De Marco 65	Italy (Verona Diabetes Study)	7,158 patients with T2DM; follow‐up, 5 years	SMR for cirrhosis as high as 2.5 (95% CI, 2.0–3.2), and higher than that observed for cardiovascular disease.	No correction for prevalence of hepatitis virus infection and cirrhosis prior to diabetes
El‐Serag 66	U S A. (Dept. of Veterans Admin. Affairs)	173,643 patients with and 650,620 without DM; follow‐up, 10–15 years.	Acute liver failure identified by ICD‐9 570. The cumulative risk of ALF significantly higher among patients with diabetes (HR, 1.44; 95% CI, 1.26–1.63). This risk is maintained after excluding patients with liver disease or hepatitis during follow‐up.	After excluding the first year of follow‐up, diabetes increases the risk of ALF, independently of recognized underlying chronic liver disease or viral hepatitis.
Caldwell 67	U S A (Liver disease registry)	2,380 patients, 167 with NASH, 215 with CC; follow‐up, 8 years.	Five middle‐aged women, with no history of liver disease, died of subacute liver failure	Obesity‐related liver disease may infrequently present as severe, subacute illness.
Jepsen 68	Denmark (Danish National Registry)	7,372 subjects with a diagnosis of fatty liver; follow‐up, up to 16 years	All causes SMR for non‐alcoholic or unspecified liver disease, 2.6 (95% CI, 2.4–2.9). In the same group, hepatobiliary SMR are as high as 19.7 (15.3–25.0). No differences in relation to T2DM.	Mortality remains increased after censoring patients upon diagnosis of liver cirrhosis. Cases with unspecified fatty liver might have biased the results
Ioannou 69	U S A (NHANES I cohort)	11,465 persons aged 25–74 years without evidence of cirrhosis at entry; mean follow‐up, 12.9 years	Cirrhosis‐related deaths or hospitalizations more common in obese persons (adjusted HR: 1.69; 95% CI, 1.0–3.0). The association is confined to persons with no or moderate alcohol consumption (adjusted HR: 4.1, 95% CI 1.4–11.4).	Obesity is a risk factor for cirrhosis‐related death or hospitalization among persons who consume little or no alcohol. The use of a combined primary outcome is subject to criticism
Dam‐Larsen 70	Denmark	215 patients with biopsy‐proven pure fatty liver (109 non‐alcoholic); median follow‐up, 16.7 years	Survival estimates different between alcoholic and non‐alcoholic fatty liver. Survival estimates in the non‐alcoholic fatty liver group are not different from the Danish population.	The study supports the concept that pure fatty liver may have a benign clinical course.

ALF = acute liver failure; BMI = body mass index; CC = cryptogenic cirrhosis; CI = confidence interval; DM = diabetes mellitus; HR = hazard ratio; ICD‐9 = International classification of diseases (9^th edition); NASH = non‐alcoholic steatohepatitis; SMR = standardized mortality rate; T2DM = type 2 diabetes mellitus.

Table II. Progression to hepatocellular carcinoma and HCC‐related mortality in metabolic disorders.

Author (ref)	Area	Population	Result	Comment
Sasaki 64	Japan (Osaka prefecture)	Population‐based study on 32,222 death certificates of patients with diabetes; observation period, 30 years	Death rate for HCC increases from 0.5% in the period 1960–64 to 3.2% in 1985–89.	No data on other risk factors for HCC in the population. The risk of ascertainment bias is elevated.
Moller 75	Denmark	37,957 obese persons, compared to the total Danish population; follow‐up, 4.8 years.	Relative risk for HCC, 1.9 (95% CI, 1.5–2.5). Results are unchanged by restriction to a subcohort of 8,207 persons where obesity is the primary discharge diagnosis, and are also similar irrespective of first year of follow‐up.	Overall, the incidence of cancer is increased by 16% in the cohort. Selection bias is not likely to have influenced the results.
Adami 76	Sweden (Swedish in‐patient and Cancer Registry)	153,852 patients with diabetes compared to nationwide estimates; follow‐up, 6–24 years	SIR for HCC in diabetes, 4.1 (95% CI, 3.8–4.5). The risk is higher in men (4.7, 4.2–52) than in women (3.4, 2.9–3.9).	After exclusion of subjects with alcoholism, cirrhosis and hepatitis, the risk continues to be three‐fold increased.
La Vecchia 77	Italy	Point‐prevalence case‐control study (428 with incident HCC and 1,502 controls); observation period, 13 years	In diabetes, OR for HCC, 2.1 (95% CI, 1.4–3.2) after adjustment for confounders, including history of hepatitis and liver cirrhosis, body mass index and history of liver cancer in first‐degree relatives.	A history of diabetes mellitus can explain about 8% (95% CI 5–11) of cases of liver cancer in this population.
Wideroff 78	Denmark	109,581 hospitalized subjects with diabetes; follow‐up, 4–16 years.	SIR for HCC, 4.0 (95%, 3.5–4.6) in males and 2.1 (95% CI = 1.6–2.7) in females. SIR remains elevated after exclusion of patients with reported risk factors (e.g., cirrhosis and hepatitis) or patients whose cancers were diagnosed at autopsy.	Patients hospitalized with a diagnosis of diabetes are at higher risk of developing HCC. The elevated risk may be confounded by obesity.
Braga 79	Italy(Northern Area)	Case‐control of 320 HCC and 1,408 controls; observation period, 1984–93)	Population‐ARs of HCC, 18% for cirrhosis, 16% for hepatitis, 8% for diabetes and 7% for heavy alcohol consumption. Compared with females, males had higher AR for cirrhosis (21% versus 11%), diabetes (10% versus 2%) and heavy alcohol intake (9% versus 1%).	Even if available information on dietary factors was limited, and the AR were based on arbitrary assumptions, diabetes control might significantly reduce the burden of HCC in Northern Italy.
Lagiou 80	Greece	Point‐prevalence case‐control study (333 incident HCC and 360 controls); 4‐year observation period.	History of diabetes associated with HCC (adjusted OR, 1.86; 95% CI, 0.99–3.51). The association is not confounded by any major risk factor (hepatitis B and C, alcohol consumption)	The authors speculate that diabetes may increase HCC risk either via hyperinsulinemia, or via NASH and non‐alcoholic cirrhosis
El‐Serag 81	U S A (Dept. of Veterans Affairs)	Point‐prevalence, case‐control study (823 HCC, 3,459 controls); observation period, 3 years	In diabetes adjusted OR for HCC, 1.57(95% CI, 1.08–2.28) only in the presence of other etiologic factors (virus, alcohol). The combined presence of HCV and alcoholic cirrhosis further increases the risk (OR 79.2, 60.3–103.4).	Diabetes increases the risk of HCC only in the presence of other risk factors. Alcohol exerts a primary role in this population
Nair 82	U S A (National transplant registry)	19,271 patients with cirrhosis (28% obese; 19% alcoholic, 13% cryptogenic cirrhosis)	OR for HCC in obese patients with alcoholic cirrhosis (3.2; 95% CI, 1.5‐6.6) and cryptogenic cirrhosis (11.1, 1.5‐87.4)	No effect of obesity on HCC in cirrhosis of different etiology
Calle 83	U S A (American Cancer Society Study)	Prospective study of 900,053 adults; follow‐up, 16 years	Death risk for HCC increased both in males (P for trend<0.001) and in females (P<0.04) with increasing BMI class. Compared to normal weight, a BMI in the range 30‐35 kg/m^2 gives a RR of 1.90 (95% CI, 1.46‐2.47) in males and 1.40 (0.97‐2.00) in females.	Increased body weight is associated with increased death rates for all cancers combined and for cancers at multiple specific sites. The risk for HCC is particularly relevant in severely obese persons
Verlato 84	Italy (Verona Diabetes Study)	7,148 patients with T2DM; follow‐up, 10 years	SMR for overall malignancies increased in females, but not in men. Excess mortality from hepatic cancer (SMR, 1.86, 95% CI, 1.44‐2.38) observed in both men and women.	No adjustment for other etiologic factors (alcohol, virus)
Sorensen 85	Denmark (Danish National Registry)	7,326 subjects with fatty liver; follow‐up, 1‐16 years	SIR for HCC elevated in patients with alcoholic (9.5, 95% CI, 5.7‐14.8) as well as non‐alcoholic fatty liver (4.4; 1.2‐11.4), compared with general Danish population.	Patients were censored upon diagnosis of cirrhosis; accordingly, the potential sequence of fatty liver to cirrhosis to HCC was missed.
Regimbeau 86	France	210 patients with liver resection for HCC; 18 (8.6%) with no underlying cause of liver disease	The prevalence of obesity (50% vs. 14%) and diabetes (56% vs. 11%) are higher in patients with cryptogenic liver disease than in patients chronic viral hepatitis (P<0.0001).	Obesity and diabetes may be important risk factors for cryptogenic chronic liver disease progressing to HCC
Coughlin 87	U S A (Cancer Prevention Study II)	467,922 men and 588,321 women; follow‐up, 16 years	Diabetes significantly associated with fatal HCC in men (RR, 2.19; 95% CI, 1.76‐2.72), but not in women (RR, 1.37; 0.94‐2.00)	The association is not explained by high body mass index, suggesting that diabetes is an independent predictor of mortality from cancer
Jee 88	Korea (National Health Insurance Co.)	1,298,385 Koreans; follow‐up, up to 10 years	Death rates from all cancers combined increased in subjects with fasting glucose > 140 mg/dl (HR, 1.29; 95% CI, 1.22‐1.37 in men and 1.23, 1.09‐1.39 in women). By cancer site, the association is confirmed for HCC (Males: HR, 1.59; 1.45‐1,74; Females: 1.28, 1.00‐1.66)	In Koreans, a population with a low BMI, elevated fasting serum glucose levels and a diagnosis of diabetes are independent risk factors for HCC.
Davila 89	U S A (Medicare database)	2,061 HCC and 6,183 controls; population‐based, case‐control study; age⩾65 years; observation period, 1994‐99	After adjustment for HBV, HCV, alcohol and hemochromatosis, OR for diabetes, 2.87 (95% CI, 2.49‐3.30). Similar data in analysis restricted to diabetes between 2‐3 years from HCC	Diabetes is independently associated with HCC, regardless of other major risk factors in the elderly. Several features of MS also increase HCC risk.

AR = attributable risk; BMI = body mass index; CI = confidence interval; HCC = hepatocellular carcinoma; HR = hazard ratio; MS = metabolic syndrome; NASH = non‐alcoholic steatohepatitis; OR = odds ratio; RR = relative risk; SIR = standardized incidence ratio; SMR = standardized mortality rate; T2DM = type 2 diabetes mellitus.

Figure 1 Interaction between genes, virus and lifestyle in the initiation and progression of metabolic liver disease. Insulin resistance is the core of the mechanism. Genes, through various and largely undefined polymorphisms, may cause or favor insulin resistance. Hepatitis‐C virus, either by its viral genome, or via increased TNF‐α production, may interfere with insulin signaling. Finally lifestyle, through obesity, adipokines and increased release of TNF‐α, produces or enhances insulin resistance. Increased FFA flux promotes steatosis (possibly aggravated by HCV‐dependent interference with the hepatic assembly and secretion of triglyceride‐rich very‐low‐density lipoproteins); hyperglycemia induces oxidative stress, hyperinsulinemia favors fibrosis and hepatic hyperplasia, both leading from fatty liver to non‐alcoholic steatohepatitis, fibrosis, cirrhosis and eventually to hepatocellular carcinoma. FFA = free fatty acids; HCV = hepatitis C virus; TNF = tumor necrosis factor; NASH = non‐alcoholic steatohepatitis; HCC = hepatocellular carcinoma; IRS‐1 = insulin receptor substrate‐1; PI‐3K = phosphatidyl inosytol‐3 kinase; PPAR = peroxisome‐proliferator activated receptor.

Table III. Clinical studies on treatment of non‐alcoholic fatty liver disease with lifestyle/weight loss modifications and insulin‐sensitizers, published in extension in peer‐reviewed journals.

Treatment	No. of cases	Type of study	Duration of treatment	Result
First author (ref)
Weight loss or lifestyle modifications
Eriksson 114	3	Observational	6–12 months	Weight loss decreases ALT and improves histology.
Palmer 115	39	Observational	Unspecified	In overweight adults, weight loss > 10% corrects hepatic abnormalities
Ueno 116	15	Controlled against cases who refused treatment (n = 10)	3 months	Weight‐losing diet and intensive physical activity. Biochemistry and histology (only steatosis) significantly better in the experimental arm
Franzese 117	38	Observational	6 months	In obese children, ALT and ‘bright liver’ improve with weight loss
Knobler 118	49	Observational	24 months	Improved biochemistry with dietary intervention and drugs (if indicated to treat associated diseases)
Kugelmans 119	16	Observational, with/without vitamin E	3 months	Improved biochemistry with lifestyle changes (diet and physical exercise); no extra advantage of vitamin E
Hickman 120	14	Observational	15 months	Improved biochemistry, health‐related quality of life, and histology with lifestyle modifications
Insulin‐sensitizers
Glitazones
Caldwell 121	10	Observational	6 months	Biochemistry improves significantly: no significant differences in histology
Neuschwander –Tetri 122	25	Observational	12 months	Both biochemistry and histology (including fibrosis and necroinflammation) improve
Promrat 123	18	Observational	12 months	Both biochemistry and histology (including fibrosis and necroinflammation) improve
Metformin
Marchesini 124	14	Controlled against cases who refused treatment (n = 6)	4 months	Metformin significantly improves ALT, reduces liver volume and decreases insulin resistance
Uygun 125	17	RCT versus diet alone (n = 17)	6 months	Metformin significantly better on ALT. Liver histology similarly improves in both arms
Nair 126	15	Observational	12 months	No differences in the long term
Bugianesi 127	55	RCT versus prescriptive diet or vitamin E (n = 55)	12 months	All subjects received nutritional counseling. Metformin significantly favors the general improvement in ALT. Histology (including fibrosis and necroinflammation) improves in a subgroup of subjects of the metformin arm

ALT = Alanine aminotransferase; RCT = randomized controlled trial.

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