Hepatic phenotypes of HNF1B gene mutations: A case of neonatal cholestasis requiring portoenterostomy and literature review

Table 1 Laboratory data before and after portoenterostomy sec. Kasai that was performed at age 32 d

Age	Total bilirubin,μmol/L	Conjugated bilirubin,μmol/L	AST,μkat/L	ALT,μkat/L	GGT,μkat/L	ALP,μkat/L	Urea, mmol/L	Creatinine,μmol/L	Cholesterol, mmol/L	Albumin, g/L	INR	Mg, mmol/L
4 d	104	32	1.27	0.42	23.3	2.3	4.7	81	2.7	36.0	0.91	NA
27 d	145	100	1.57	0.92	10.2	7.2	2.2	29	3.7	36.8	1.05	NA
5 mo	135	110	2.59	2.24	6.8	8.1	5.2	22	9.5	42.0	0.84	NA
19 mo	30	25	3.15	3.09	7.5	11.4	5.3	18	6.7	42.7	0.95	0.90
2 yr	33	28	3.10	3.13	6.4	10.7	5.5	21	6.7	43.9	0.92	0.66

NA: Not available; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; ALP: Alkaline phosphatase; INR: International normalized ratio.

Table 2 Phenotypic outline in twelve patients with hepatic involvement due to HNF1B mutation or whole gene deletion

Ref.	Sex/Origin	GW/BW g (BW SDS) (Lawrence 1989)	First clinical symptoms (age)	Laboratory results	Kidney ultrasound	Kidney function	Liver biopsy	Pancreas morphology	Pancreatic exocrine function	Onset of clinical diabetes (age)	Diabetes treatment	Intellectual development	Genotype (inherited from)
Severe neonatal cholestatic icterus
Present report	F/Czech	38/2360 (-2.02)	Neonatal cholestasis (first week of life)	Anemia; progressively increasing, mainly cholestatic, liver tests	Multiple bilateral cortical cysts (maximal diameter 5 mm), prenatally hyperechogenic kidneys	Normal by 2 yr	Paucity of intrahepatic bile ducts, severe biliary stasis, marked periportal fibrosis	Absent body and tail	Normal fecal elastase by age 19 mo	Normoglycaemia by 2 yr	Not applicable	Normal	1698 kb deletion including HNF1B (de novo)
[17]	M/Sardinian	37/1520 (-3.70)	Neonatal cholestasis (first weeks of life)	High but resolving hyperbilirubinemia; fluctuating liver enzymes; high triglyceridemia	Left kidney agenesis; enlarged and hyperechogenic right kidney; multiple cortical cysts	Progressive chronic renal insufficiency by 18 yr	Paucity of intrahepatic bile ducts, severe biliary stasis, slight periportal fibrosis	Progressive atrophy from birth up to 16 yr	Progressive decline; need for enzyme replacement by 16 yr	Transient neonatal hyperglycemia; permanent diabetes since 5 yr	Insulin 1.26 U/kg per day by 18 yr	NA	c. 499_504delGCTC TGinsCCCCT (de novo)
[16]	M/Japanese	39/2390 (-2.54)	Neonatal respiratory distress; neonatal cholestasis (first weeks of life)	Hyperbilirubinemia (resolving by 9 mo); transiently high cholesterol; constantly high AST, ALT	Multiple bilateral cysts (right, four cysts of 10-20 mm diameter; left, one cyst of 10 mm diameter)	Mild chronic renal insufficiency by 13 yr	Marked cholestasis; reduced number of intrahepatic bile ducts; no signs of infiltration	NA	NA	13 yr	Insulin 0.4 U/kg per day after therapy onset	Slightly delayed	c. 457C>A (de novo or paternal)
Late-onset cholestasis
[18] case No. 1	M/German	35/1780 (-2.08)	Neonatal cholestasis (first weeks of life)	Elevated AST/ALT/GGT	Cystic dysplasia; hydronephrosis due to urethral stenosis	Chronic renal insufficiency by 18 yr	Intrahepatic cholestasis due to paucity of bile ducts	Hypoplastic	Fecal elastase deficiency	13 yr	Insulin 1.34 U/kg per day by 18 yr	Retarded	1590 kb deletion including HNF1B (de novo or paternal)
[20] case No. 1	F/?	NA	Jaundice (29 yr)	Progressively increasing, mainly cholestatic, liver tests; hypomagnesaemia	Renal cysts	Mild chronic renal insufficiency by 33 yr	Non-specific changes; slight steatosis	Atrophic	NA	14 yr	NA	Normal	1423 kb deletion including HNF1B (NA)
[20] case No. 2	M/?	NA	"Chronic pancreatitis" (44 yr)	Progressively increasing, mainly cholestatic, liver tests; hypomagnesaemia	Renal cysts	Mild chronic renal insufficiency by 53 yr	Minor sinusoidal dilatation	Atrophic	NA	51 yr	NA	Retarded	1427 kb deletion including HNF1B (NA)
Non-cholestatic liver impairment
[20] case No. 3	F/?	NA	Jaundice (30 yr)	Progressively increasing cholestatic liver tests; hypomagnesaemia	Renal cysts	Chronc renal insufficiency by 30 yr	Thickened basal membranes around the bile ducts; minor sinusoidal dilatation	Atrophic	NA	Before 30 yr	NA	Normal	c. 544C>T (NA)
[18] case No. 2	F/Turkish	40/2630 (-2.13)	Unilateral cystic kidney dysplasia; diabetes (13 yr)	Elevated AST/ALT	Unilateral cystic dysplasia	Normal by 15 yr	No cholestasis	Normal	Normal	13 yr	Insulin 0.24 U/kg per day by 15 yr	Normal	1700 kb deletion including HNF1B (de novo)
[18] case No. 3	F/Vietnamese	40/2600 (-2.20)	Prolonged severe hyperglycemia; bilateral cataracts (16 yr)	Elevated AST/ALT/GGT	Bilateral cortical cysts	Mild chronic renal insufficiency by 16.5 yr	No cholestasis	Absent body and tail	Fecal elastase deficiency	16 yr	Insulin 3.4 U/kg per day by 16.5 yr	Normal	1310 kb deletion including HNF1B (de novo)
[18] case No. 4 and [28]	M/German	38/2650 (-1.53)	Failure to thrive and renal failure (4 wk)	Elevated AST/ALT/GGT	Hypoplastic hyperechogenic kidneys; cortical cysts	End-stage renal failure - dialysis since 10 yr, transplantation at 10.5 yr	Steatohepatitis	Normal	Normal	15 yr	Insulin 0.2 U/kg per day by 15 yr	Retarded	1550 kb deletion including HNF1B (de novo)
[18] case No. 5	F/German	40/3340 (-0.40)	Unilateral coloboma and loss of vision; diabetes (12 yr)	Elevated AST/ALT	No visible renal abnormity; arterial hypertension	Normal by 15.6 yr	Steatohepatitis	Normal	Normal	12 yr	Insulin 0.4 U/kg per day by 15.6 yr	Normal	1430 kb deletion including HNF1B (de novo or paternal)
[19]	F/Turkish	38/1900 (-3.13)	Fever; diarrhea; failure to thrive (3 mo)	Anemia; leucocytosis; renal and hepatic dysfunction; acidosis; hyperglycemia	Hypoplastic hyperechogenic kidneys; cortical cysts	Progressive chronic renal insufficiency by 7 yr	Mild steatosis; iron deposition in hepatocytes and Kupffer cells; persistent hematopoiesis	Atrophic head; absent body and tail	Fecal elastase deficiency	Transient hyperglycemia at 3 mo; permanent diabetes since 6 yr	Insulin 0.42 U/kg per day after therapy onset	NA	c. 443C>T (de novo)

BW: Birth weight; GW: Gestational week; NA: Information is not available; SDS: Standard deviation score; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.