Outcomes of patients with post-hepatectomy hypophosphatemia: A narrative review

Table 1 Summary of study characteristics of all included studies in the literature review

No	Ref.	Definition of HP	PHH, n (%)	NP, n (%)	Type of liver resection (%)	Histopathology (%)	Post-operative phosphate replacement regime	Phosphate replacement, n (%)
1	Buell et al[14], 1998	< 2.5 mg/dL	21/35 (60)	14/35 (40)	Major hepatectomy (NR); Cryosurgery (NR)	CRLM: 8 (23) HCC: 4 (11) Others: 23 (66)	For phosphate < 3.0 mg/dL: sodium phosphate or potassium phosphate HP: mean of 15 mmol/d on POD1, to 25 mmol/d on POD3 NP: mean of 5 mmol/d	NR
2	George et al[11], 1992	NR	44/44 (100)	0	Right hepatectomy and extended right hepatectomy	NR	NR	NR
3	Giovannini et al[12], 2002	Normal: > 2.5 mg/dL; Mild-moderate: 1.6-2.5 mg/dL; Severe: < 1.5 mg/dL	38/59 (64.4)	21/59 (35.6)	Major hepatectomy (58); Minor hepatectomy (42)	CRLM: 10 (17) ICC: 7 (12) HCC: 16 (27) GBC: 2 (3) Others: 24 (41)	If > POD3 and oral feeding cannot be resumed: parenteral phosphate (fructose 1-6 diphosphate or potassium phosphate) at 20-50 mmol/d	NR
4	Hallet et al[10], 2016	≤ 0.65 mmol/L	223/402 (55.5)	179/402 (44.5)	Major hepatectomy (52) Minor (48) Hepatectomy	CRLM: 260 (65) ICC: 53 (13) HCC: 27 (7)Others: 62 (15)	Based on serum phosphate: Intravenous potassium phosphate or sodium phosphate	NR
5	Serrano et al[38], 2019	Normal: > 2.5 mg/dL; Mild: 1.6-2.5 mg/dL; Moderate: 1.0-1.5 mg/dL; Severe: < 1.0 mg/dL	161		Living donor hepatectomy	NA	Elemental phosphate based on phosphate levels: < 1.1 mg/dL: 25 mmol 1.1-1.9 mg/dL: 20 mmol 2.0-2.3 mg/dL: 15 mmol 2.4-2.7 mg/ dL: 10 mmol	NR
6	Squires et al[13], 2014	Normal: > 2.5 mg/dL; Mild: 1.6-2.5 mg/dL; Moderate: 1.0-1.5 mg/dL; Severe: < 1.0 mg/dL	488/719 (67.9)	231/719 (32.1)	Extended left hepatectomy (6) Extended right hepatectomy (20) Left hemihepatectomy (23) Right hemihepatectomy (39) Central hepatectomy (2) Non-anatomical (10)	CRML: 229 (32) HCC: 69 (9) ICC: 88 (12) Metastatic NET: 34 (5) Other: 299 (42)	Discretion of surgeon Median replacement: 55 mmol (range 10-170 mmol)	469 (69)
7	Tan et al[39], 2003	Normal: > 2.5 mg/dL; Moderate: 1.5-2.5 mg/dL; Severe: 1.0-1.5 mg/dL; Profound: < 1.0 mg/dL	89/95 (93.7)	6/95 (6.3)	Right-lobe living donor hepatectomy: Right hepatectomy (94); Left lateral segmentectomy (5); Left lobectomy (11)	NA	Based on phosphate deficit: intravenous or oral phosphate	NR
8	Yuan et al[40], 2010	Normal: > 2.5 mg/dL; Mild: 1.5-2.5 mg/dL; Moderate: 1.0-1.5 mg/dL; Severe: < 1.0 mg/dL	Overall: 100/102 (98) Mild: 56/102 Moderate: 25/102 Severe: 19/102	2/102 (2)	Living donor hemi-hepatectomy	NA	Severe HP: Intravenous phosphate	7/19 (36.8)

All categorical variables are expressed as n (%). CRLM: Colorectal liver metastasis; GBC: Gallbladder carcinoma; HCC: Hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma; ILI: Initial liver insufficiency; INR: International normalized ratio; LOS: Length of stay; NA: NET: Neuroendocrine tumor; Not applicable; NP: Normophosphatemia; NR: Not reported; PHH: Post-hepatectomy hypophosphatemia; PHLF: Post-hepatectomy liver failure.

Table 2 Summary of laboratory values and post-operative outcomes comparing patients with post-hepatectomy hypophosphatemia and normophosphatemia

		Mean nadir phosphate, mg/dLa			Mean INRa			Length of stay, d			Post-hepatectomy liver failure			Any morbidity			30 d mortality
No	Ref.	PHH	NP	P value	PHH	NP	P value	PHH	NP	P value	PHH	NP	P value	PHH	NP	P value	PHH	NP	P value
1	Buell et al[14], 1998	2.1 ± 0.1b	3.0 ± 0.2b	< 0.05	NR			16.22 ± 12.09	11.22 ± 7.03	NR	NR			17/21 (81)	4/14 (29)	< 0.05	1/21 (5)	0/14 (0)	NR
2	George et al[11], 1992	NR			NR			NR			1/44 (2)	0/0	NA	11/44 (25)	0/0 (0)	NA	NR
3	Giovannini et al[12], 2002	1.7 ± 0.8 (POD3)		NR	NR			NR			NR			Mild-moderate: 4/23 (17) Severe: 9/15 (60)	3/21 (14)	< 0.001c	Mild-moderate: 1/23 (4) Severe: 3/12 (20)	1/21 (5)	NR
4	Hallet et al[10], 2016	1.52 ± 0.31d	2.72 ± 0.74d	< 0.01	1.51 ± 0.37	1.53 ± 0.91	0.83	7 (6-10)	7 (5-11)	0.55	44/223 (19.7)	20/179 (11.2)	0.02	Major morbidity: 13/223 (5.8)	Major morbidity: 12/179 (6.7)	0.56	9/223 (4.0)	4/179 (2.2)	0.31
5	Serrano et al[38], 2019	2.00e (recorded at median 1.6 d post-operatively)			NR			7.2 ± 3.4e		NR	10/161 (6.2)		NR	Any morbidity > 30 d: 19/161 (11.8)		NR	NR
6	Squires et al[13], 2014	2.2 [1.7-2.8]			NR			NR			Moderate: 8.0% Severe: 8.5% Profound: 3.4%f	12.3%f	0.008	Major morbidity: Moderate: 20.1% Severe: 19.5% Profound: 16.7%f	30.3%f	0.037	Moderate: 3.8% Severe: 2.8% Profound: 0%	6.5%	0.010
7	Tan et al[39], 2003	2.6 (range 1.3-5.0)		NR	NR			NR			NR			Any morbidity: 8/95 (8.4)		NR	NR
8	Yuan et al[40], 2010	1.89 ± 0.72 (POD3)		NR	Mild: 1.51 ± 0.26 Moderate: 1.43 ± 0.19 Severe: 1.95 ± 0.40	NR	< 0.001g	NR			14/100 (14)	0/2 (0)	NR	NR			NR

^aValues are reported on post-operative day 2 unless otherwise specified.

^bValues described here excluded patients who received cryosurgery; the study included cohort of patients who received both major hepatectomy and cryosurgery.

^cComparing severe PHH (< 1.5 mg/dL) with other range of phosphate values.

^dValues were reported in mmol/L in the original study and subsequently converted to mmol/L for standardization.

^eOverall mean and SD was calculated through the combination of mean and SD from patients who had liver insufficiency and those without using methods described by Michael et al[37].

^fExact values of patients with normal, moderate, severe and profound post-hepatectomy hypophosphatemia (PHH) were not provided in the study.

^gComparing between each subgroup of PHH. All categorical variables are expressed as n (%), and all continuous variables are expressed in median (range), median [IQR], or mean ± SD unless otherwise specified. NA: Not applicable; NP: Normophosphatemia; NR: Not reported; PHH: Post-hepatectomy hypophosphatemia; POD: Post-operative day; SD: Standard deviation.

Table 3 Summary of phosphate replacement regimes for hypophosphatemia

Indications		Formulation	Route of administration	Composition	Recommended dosage	Special considerations
Mild hypophosphatemia (0.65-0.81 mmol/L)		Phospho-soda (C.B. Fleet Company, Virginia)	Oral	180mg Na2HPO4 · 7H2O + 480 mg NaH2PO4 · H2O/mL Phosphate: 4.150 mmol/mL Sodium: 4.822 mEq/mL Potassium: 0	1000mg/d	Chronic renal failure / reduced glomerular filtration rate: to use half of recommended initial dose Causes diarrhoea
		Phospha 250 Neutral (Rising Pharmaceuticals, Inc., United States)	Oral	Elemental phosphorus 250 mg (8 mmol), Sodium 298 mg (13 mEq), and Potassium 45 mg (1.1 mEq)
Moderate hypophosphatemia (0.32-0.65 mmol/L)	Not on ventilator	Phospho-soda (C.B. Fleet Company, Virginia)	(same as above)	(same as above)	If ≥1.5 mg/dL: 1 mmol/kg of elemental phosphorus (minimum of 40 mmol and a maximum of 80 mmol) in 3-4 doses over 24 h If < 1.5 mg/dL: 1.3 mmol/kg of elemental phosphorus (maximum of 100 mmol) in 3-4 doses over 24 h	(same as above)
	On ventilator	Sodium phosphate (Abbott Laboratories, North Chicago, Illinois)	Intravenous	142 mg Na2HPO4 + 276 mg NaH2PO4 · H2O/mL Phosphate: 3.0 mmol/mL Sodium: 4.0 mEq/mL	0.08 mg/kg over 2-6 h if recent and uncomplicated HP 0.16 mg/kg over 2-6 h if prolonged and has multiple causes Maximum of 20 mmol/h	Chronic renal failure / reduced glomerular filtration rate: to use half of recommended initial dose
		Potassium phosphate (Invenex Pharmaceuticals, Grand Island, New York)		236 mg K2HPO4 + 224 mg KH2PO4/mL Phosphate: 3.003 mmol/mL 4.360 mEq/mL		Chronic renal failure / reduced glomerular filtration rate: to use half of recommended initial dose To avoid if potassium > 4mmol/L
Severe hypophosphatemia (< 0.32 mmol/L) / Critically ill patients, or with severe complications of hypophosphatemia		Sodium phosphate or potassium phospahte	(same as above)	(same as above)	0.08-0.16 mg/kg over 2-6 h	(same as above)